ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH











ONCOLOGIC DRUGS ADVISORY COMMITTEE 

58TH MEETING



















Tuesday, September 2, 1998

8:00 a.m.







Holiday Inn Bethesda
Versailles I, II, III
8120 Wisconsin Avenue
Bethesda, Maryland

PARTICIPANTS

Janice Dutcher, M.D., Chairperson
Karen Templeton-Somers, Executive Secretary

MEMBERS

   Kathy S. Albain, M.D.
   David H. Johnson, M.D.
   Kim A. Margolin, M.D.
   Robert Ozols, M.D.
   Richard L. Schilsky, M.D.
   Richard Simon, D.Sc.
   Derek Raghavan, M.D., Ph.D.

   E. Carolyn Beaman, Consumer Representative
   Deborah Cassel, Patient Representative
   Sandra Zook-Fischler, Patient Representative

CONSULTANTS

   George Sledge, M.D.
   Carole Miller, M.D.
   Julie M. Vose, M.D.
   Steven E. Lipschultz, M.D.

GUEST EXPERTS

   Susan Ashley
   Trevor Powles, M.D.
   Timothy O'Leary
   James H. Doroshow, M.D.
   James L. Weiss, M.D.

FDA

   Rachel Behrman, M.D., M.P.H.
   Julia Goldstein, M.D.
   Susan Honig, M.D. 
   Susan Jerian, M.D.
   Robert Justice, M.D.
   Kathryn Stein, M.D.
   Patricia Keegan
   Jay Seigel, M.D.
   John Johnson, Clinical Team Leader
   Julie Beitz, Medical Team Leader

C O N T E N T S

A.M. SESSION
NDA Supplement 17-970/S-040 Nolvadex (tamoxifen)
Zeneca Pharmaceuticals

Call to Order and Introductions, Janice Dutcher, M.D.	5

Conflict of Interest Statement, 
   Karen M. Templeton-Somers	7

Open Public Hearing:

   Marilyn McGregor	8
   Carolyn Aldige	12
   Samuel Epstein (letter)	15
   Barbara Brenner (letter)	20

Sponsor Presentation:

   Introduction, Jerry Lewis, M.D.	24

   Summary of the Breast Cancer Prevention Trial
      Results, Joseph Costantino, Dr. P.H., NSABP	27

   Summary, Jerry Lewis, M.D.	47

Questions from the Committee	48

FDA Presentation, Susan Honig, M.D.	88

Comments on the Royal Marsden Study,
   Trevor Powels, M.D.	124

Questions from the Committee	132

Open Public Hearing:

   Ann E. Fonfa	149
   Cynthia Pearson	154
   Vincent Li	161
   Helen Schiff	161
   Mary Ann Napoli	169
   Sharon Batt	172

Committee Discussion and Vote	175
   (ODAC Discussants: Kathy Albain, M.D. 
    and George Sledge, M.D.)

P.M. SESSION
Biologics License Application (BLA) 98-0369
Herceptin (trastuzumab)
Genentech, Inc.

Call to Order and Introductions, Janice Dutcher, M.D.	232


C O N T E N T S (Continued)

Conflict of Interest Statement,
   Karen Templeton-Somers, Ph.D.	233

Open Public Hearing:

   Alice Hamele (letter)	235
   Rosemary Locke	238
   Elaine Doubrava (letter)	239
   Marilyn McGregor	241
   Philip Wyatt (letter)	244

Introduction of the Issues, Julia Goldstein, M.D.	247

Sponsor Presentation:

   Introduction and Regulatory History, Karl G. Trass	254

   Scientific Rationale and Clinical Efficacy,
      Steven Shak, M.D.	257

   Clinical Safety, Virginia Paton, Pharm. D.	276

   Summary of Benefits and Risks, Steven Shak, M.D.	292

Questions from the Committee 	295

FDA Presentation, Susan Jerian, M.D.	324

Questions from the Committee	357

Open Public Hearing:

   Robert Erwin	370

Committee Discussion and Vote	375
   (ODAC Discussants: Janice Dutcher, M.D. and 
      Carole Miller, M.D.





P R O C E E D I N G S
Call to Order and Introductions
	DR. DUTCHER:  Good morning.  In case you are in 
the wrong room, this is the Oncologic Drugs Advisory 
Committee.  We are going to start a three-day meeting.  Two 
of our committee members were unable to make it here because 
they live in cities that are served only by Northwest 
Airlines, Drs. Krook and Santana.  They send their regards.
	As I am sure everyone in the room is aware, we 
have a tremendous amount of material to cover today, and our 
goal is to carefully evaluate the data that are presented by 
both the sponsor and FDA, and that is the goal of both the 
committee and the audience. 
	We do have a large number of members of the public 
who requested to speak and participate, which we welcome.  
We are going to ask that everyone, including members of the 
committee and members of the audience, to be as succinct 
with their comments as possible so that we can get through 
what should be a very interesting and pretty power-packed 
day full of information.  So, we hope that everyone will 
work together so that we are not all here until midnight.  
Thank you all for your interest and for your willingness to 
participate. 
	We will go around the room and introduce the 
members of the committee.  I am Janice Dutcher, from Albert 
Einstein Cancer Center, in New York. 
	DR. JOHNSON:  David Johnson, Vanderbilt 
University, Nashville.
	DR. MARGOLIN:  Kim Margolin, City of Hope, Duarte, 
California.
	DR. ALBAIN:  Kathy Albain, Loyola University of 
Chicago.
	DR. SIMON:  Richard Simon, National Cancer 
Institute.
	DR. SCHILSKY:  Richard Schilsky, University of 
Chicago.
	DR. OZOLS:  Bob Ozols, Fox Chase Cancer Center, 
Philadelphia.
	DR. TEMPLETON-SOMERS:  Karen Somers, Executive 
Secretary to the committee, FDA.
	DR. SLEDGE:  George Sledge, Indiana University.
	DR. RAGHAVAN:  Derek Raghavan, University of 
Southern California.
	MS. BEAMAN:  Carolyn Beaman, consumer rep, Sisters 
Breast Cancer Network.
	DR. BEITZ:  Julie Beitz, Medical Team Leader, FDA.
	DR. HONIG:  Susan Honig, Medical Reviewer, FDA.
	DR. JUSTICE:  Bob Justice, Acting Director, 
Division of Oncology Drug Products, FDA.
	DR. TEMPLETON-SOMERS:  We have also two guests for 
the FDA, Dr. Trevor Powles, if you could stand up for us?  
Thank you.  And, Dr. Susan Ashley, statistician for his 
group?  Thank you. 
	DR. DUTCHER:  All right.  We are now going to read 
the conflict of interest statement. 
Conflict of Interest Statement
	DR. TEMPLETON-SOMERS:  The following announcement 
addresses the issue of conflict of interest with regard to 
this meeting and is made a part of the record to preclude 
even the appearance of such at this meeting. 
	Based on the submitted agenda for the meeting and 
all financial interests reported by the participants, it has 
been determined that all interests in firms regulated by the 
Center for Drug Evaluation and Research which have been 
reported by the participants present no potential for a 
conflict of interest at this meeting, with the following 
exceptions:
	Dr. James Krook is excluded from participating in 
today's discussions and vote concerning Nolvadex.  In 
addition, Dr. Robert Ozols has been granted a waiver that 
permits him to participate in all matters concerning 
Nolvadex. 
	A copy of this waiver statement may be obtained by 
submitting a written request to the FDA's Freedom of 
Information Office, Room 12A-30 at the Parklawn Building. 
	In the event that the discussions involve any 
other products or firms not already on the agenda for which 
an FDA participant has a financial interest, the 
participants are aware of the need to exclude themselves 
from such involvement, and their exclusion will be noted for 
the record. 
	With respect to all other participants, we ask in 
the interest of fairness that they address any current or 
previous involvement with any firm whose products they may 
wish to comment upon.  Thank you.
	DR. DUTCHER:  Thank you.  I think you can see from 
the agenda that the open public hearing has been expanded 
due to the interest in the agents being discussed today.  
So, we will start with the open public hearing, which will 
occur before the presentation, and then following the two 
presentations we will have additional comments from the 
public. 
	We will begin with the people who have requested 
to speak.  The first is Marilyn McGregor.  We would 
appreciate it if all speakers would identify themselves as 
well as any sponsorship, either the sponsor or otherwise. We 
would appreciate it if those who speak could use the podium 
if possible.
Open Public Hearing
	MS. MCGREGOR:  My name is Marilyn McGregor, and I 
am Administrative Director of the Cancer Support Community 
located in San Francisco.  I have no financial interest in 
tamoxifen. 
	There is a great longing to believe that there is 
a preventative drug for breast cancer.  Given the dismal and 
long-term unchanging mortality rate of breast cancer, there 
is a willingness to believe that this drug could be the 
answer to so many people's prayers.  But as scientists and 
as an organization responsible for the public good, I urge 
this committee not to approve the application of tamoxifen 
as a breast cancer prevention drug. 
	The reasons I urge this decision are as follows:  
There is clinical trial medicine and real life medicine and 
media over-estimation of the benefits of any one cancer 
drug.  There needs to be a higher level of assurance when 
prescribing a drug that is a known carcinogen in a healthy 
population or at least no discernible breast cancer.  Those 
of us diagnosed with breast cancer have a different 
ris/benefit ratio, and tamoxifen may be appropriate. 
	Clinical trials medicine defines exactly who 
benefits given their family history of breast cancer, as was 
done in the NCI trial.  Real life medicine has a busy doctor 
in an HMO whose patient may have no family history or risk 
factors or the pervasive anxiety about developing breast 
cancer.  This woman would most likely be prescribed 
tamoxifen as a preventative.  Off-label prescription is 
common in cancer and is a benefit to most cancer patients, 
but this may not be the case with tamoxifen as a 
preventative in a healthy population.
	The NCI study does not prove that tamoxifen 
prevents breast cancer for the life of any one woman.  The 
most that can be said of the NCI trial is that the tamoxifen 
group appeared to have less breast cancer for the short 
period of time of the trial, which was an average of 3 
years.  A woman can develop breast cancer in over a 50-year 
period.  If this drug is approved as a preventative, the 
insert should say that the drug is only to be prescribed for 
the length of time of the trial, which was approximately 3 
or 4 years. 
	Other speakers will, no doubt, discuss the British 
studies which reported no benefit of tamoxifen as a 
preventative.  I am going to discuss the Italian study of 
Dr. Bianco.  At the May, 1998 ASCO meeting in LA, there was 
a symposium on HER2.  Dr. Bianco discussed his 20-year study 
of HER2 overexpression in tamoxifen use.  Bianco and his 
colleagues found that there was no apparent benefit in using 
tamoxifen for those who overexpress HER2.  All other 
categories showed a benefit of tamoxifen use. 
	In addition, the Italian research also showed that 
those women who overexpressed HER2 and took tamoxifen had an 
overall worse outcome.  Dr. Bianco stated that his research 
could greatly affect the use of tamoxifen, and called for 
further study on this issue.
	If, indeed, the Italian studies prove to be 
accurate, this could potentially mean that 25 to 30 percent 
of women would have no benefit of tamoxifen either as 
healthy patients or cancer patients.  This could potentially 
mean that before a woman would be prescribed tamoxifen she 
would have to be tested for HER2 overexpression.  Many other 
possibilities are also possible.
	However, at this time we do not know the answers 
to these scientific questions but answers are certainly 
needed.  Good science demands more good science.  It is 
well-known in scientific circles that negative studies or 
non-U.S. studies are routinely not included in drug 
analysis.  I urge that the Italian and British studies be 
considered carefully in your application. 
	I urge the NCI to immediately conduct appropriate 
studies regarding the interaction of HER2 overexpression and 
tamoxifen use.  I recommend these studies be completed 
before any approval of tamoxifen as a preventative for 
healthy women.  Meta-analyses, retrospective tumor block 
studies and/or well-controlled trials all need to be done to 
ascertain if tamoxifen is beneficial to those women who 
overexpress HER2 in the healthy population and in the cancer 
population. 
	As tamoxifen is already licensed, doctors may 
continue to prescribe the drug in individual cases, but the 
FDA and the NCI need to protect the public.
	Thank you for consideration of my remarks.
	DR. DUTCHER:  Thank you.  The next speaker is 
Carolyn Aldige.
	MS. ALDIGE:  Good morning.  I am Carolyn Aldige, 
President and Founder of the Cancer Research Foundation of 
America.  Additionally, I have the privilege of currently 
serving a 2-year term as President of the National Coalition 
for Cancer Research. 
	The mission of CRFA, cancer prevention through 
research and education, is fueled by the knowledge that as 
much as 70 percent of all cancer is preventable.  We believe 
that prevention provides our greatest hope for reducing 
cancer's deadly impact.  We also believe that our 
organization's focus on prevention is unique among 
cancer-related organizations.  Since 1985 CRFA has directed 
more than $30 million to promising research, education and 
early detection programs that turn the promise of cancer 
prevention into reality. 
	Before making my formal comments, I should note 
for the record that CRFA receives support from a number of 
pharmaceutical companies, including Zeneca Pharmaceuticals, 
as well as a host of other corporate supporters and 
individual donors. 
	You know the challenge.  Breast cancer is the most 
common cancer among women, accounting for one out of every 
three women's cancer diagnoses in the United States.  Last 
year approximately 180,000 new cases of breast cancer were 
diagnosed, and nearly 45,000 women died from the disease.  
Only lung cancer causes more cancer deaths in women. 
	In the face of such discouraging news, the 
prospect of the first effective chemopreventive agent for 
women at risk for breast cancer, tamoxifen, is heartening 
indeed. 
	I would like to thank the Oncologic Drugs Advisory 
Committee for allowing me to speak today for this is, in 
fact, the first time I have requested permission to address 
an ODAC panel.  Why?  Because this is the first time, to my 
knowledge, the committee has considered approving a drug to 
prevent cancer.  Heretofore, consideration was given only to 
drugs that could be used for treatment.  In our view, this 
is a landmark event. 
	CRFA has long supported the National Cancer's 
Institute decision to conduct ground-breaking cancer 
prevention trials.  In fact, in 1993 I was pleased to have 
the opportunity to testify before the Senate Cancer 
Coalition in favor of continuing the breast cancer 
prevention trial. 
	We believe that the compelling results of NSABP's 
P-1 study merit approval of Zeneca's application for the use 
of Nolvadex as the first preventive agent for women at risk 
for breast cancer.  The trial results are, as Dr. Richard 
Klausner has noted, nothing less than a real advance for 
women with a family history of breast cancer.  Women in the 
trial taking tamoxifen developed 45 percent fewer cases of 
breast cancer than those on placebo.  There were 85 new 
cases in the tamoxifen group over 4 years compared with 154 
in those on placebo.  Women on tamoxifen also had fewer 
cases of DCIS, as well as fewer bone fractures of the hip, 
wrist and spine. 
	We also note that the drug has its drawbacks -- 
more cases of endometrial cancer, pulmonary embolism and 
deep vein thrombosis.  The risk for endometrial cancer in 
the tamoxifen groups was more than that of the placebo 
group, while the risk of pulmonary embolism was nearly 
tripled.  However, these potentially dangerous side effects 
appear to be limited to women older than 50, and we believe 
these risks can be managed.
	While no one can underestimate the seriousness of 
these potentially life-threatening side effects, the case 
for ODAC approval remains a strong one.  Approval will 
ensure that doctors and other health care professionals are 
fully aware of the drug's side effects, and can discuss them 
fully with patients.  Approval provides the FDA with the 
opportunity to capture data about adverse events, rounding 
out knowledge of the drug.  Approval means that patients and 
doctors will not have to seek the drug off-label 
prescriptions. 
	The approval of tamoxifen is a crucial early step 
in the prevention of breast cancer in American women.  We, 
at CRFA, applaud your taking this step which means so much 
in the long term to women at risk for the disease and their 
families. 
	Thank you again for the opportunity to speak 
today. 
	DR. DUTCHER:  Thank you.  We also have two 
letters, and Dr. Somers will read the letters. 
	DR. TEMPLETON-SOMERS:  The first letter is from 
Dr. Samuel Epstein, who is a Professor of Environmental and 
Occupational Medicine at the University of Illinois. 
	Zeneca's Nolvadex NDA for preventing breast cancer 
in healthy women "at high risk of cancer," including all 
women over 60 years old, is primarily based on NCI's April 
6, 1998 summary report, "Breast Cancer Prevention Trial, 
BCPT, Shows Major Benefits and Some Risks." 
	This report was unsupported by a peer reviewed 
scientific publication and was qualified by the admission 
that "further analyses of the data are under way."  No 
further data have yet been released, nor has the report yet 
been published.  Additional evidence is derived from 
tamoxifen's partial protective effects in rats and mice 
against the induction of breast cancer by 
7,12-dimethylbenzanthracene, DMBA, besides other 
carcinogens.  However, those DMBA-induced cancers which were 
not suppressed were hormone independent and highly 
aggressive.
	NCI's report announced that the BCPT had been 
terminated prematurely on March 24 in view of "clear 
evidence that tamoxifen reduced breast cancer risks."  As 
indicated in the Table -- and for this I will have to refer 
the committee to the tables in their packets -- based on 
data cited in the report, tamoxifen reduced the incidence of 
both invasive and non-invasive breast cancer in women of all 
ages.  However, the short term duration of the trial 
precludes determination as to whether the drug prevented 
cancer or merely delayed its onset by treating small 
undetected tumors. 
	On July 11, 1998, two publications in The Lancet 
reported no evidence for the efficacy of tamoxifen in 
preventing breast cancer.  A 6-year trial by the Royal 
Marsden Hospital, London oncologic team, based on some 2500 
women with a family history of breast cancer, and a similar 
4-year study by the European Institute of Oncology in Milan, 
based on 5400 women, reported no difference in the incidence 
of breast cancer in women treated with tamoxifen or placebo.
	An accompanying editorial warned -- this is a 
quote -- the failure of these trials to confirm the results 
of the U.S. study, however, casts doubt on the wisdom of the 
rush, at least in some places, to prescribe tamoxifen widely 
for prevention.  Longer follow-up of completed and current 
trials is clearly required to clarify the relative 
preventive benefits and risks in different populations, and 
to confirm the BCPT findings.  Most importantly, none of 
these trials provides reliable data on mortality, which 
should be the ultimate endpoint.
	These concerns have been summarily dismissed by 
NCI -- "the chance that our results occurred by chance was 1 
in 10,000."  However, The Lancet editorial did not challenge 
the results themselves, but their interpretation and 
significance. 
	Serious short-term complications in the BCPT, 
uterine cancer, pulmonary embolism and deep vein thrombosis, 
were increased 2-3-fold in the tamoxifen group.  These 
complications were only seen in postmenopausal women.  Among 
non-hysterectomized women in this age group, the incidence 
of these serious complications was 2.2 percent in contrast 
to a 1 percent reduction in the incidence of breast cancer.
	It must be recognized that the short term duration 
of the BCPT, apart from the absence of any long-term 
follow-up, precludes recognition of possible further 
increases in the incidence of already recognized short-term 
life-threatening and other serious complications, and also 
of other, not yet reported, long-term or delayed 
complications.  Of concern in this connection is the fact 
that tamoxifen induces ovarian necrosis and ovulation in a 
manner similar to clomiphene, a recognized risk factor for 
ovarian cancer.  	More serious still is the high 
hepatocarcinogenic potency of tamoxifen in the rat, as 
confirmed in February 1966 by the International Agency for 
Research on Cancer, at low doses and blood levels equivalent 
to those in the BCPT.  Tamoxifen also binds tightly to 
estrogen receptors in the human liver, and induces highly 
stable DNA adducts in 2 rodent species.  Risks of liver 
cancer are not precluded by the absence of such reported 
complications among breast cancer patients treated with 
tamoxifen as relatively few such women have taken the drug 
for over 5 years and followed up for a further 20 years 
before which the induction of liver cancer would be 
unlikely.
	It should be noted that senior NCI staffer Dr. 
Leslie Ford dismissed risks of liver cancer on the grounds 
that no cases were reported in the short term BCPT, and also 
on the incorrect grounds that carcinogenic effects in rats 
were only seen at high doses.  Ford's logic, however, would 
exculpate virtually all recognized human carcinogens.  
Furthermore, NCI's denigration of the human relevance of the 
experimental carcinogenicity data on tamoxifen and its 
failure to warn BCPT participants of this grave risk is in 
striking contrast to its reliance on rodent teratogenicity 
data as the basis for warning against the administration of 
tamoxifen to pregnant women. 
	It is of further interest to note that while some 
25 cases of liver toxicity in tamoxifen-treated breast 
cancer patients, acute hepatitis, liver failure and deaths 
and hepatobiliary complications, have been reported in the 
U.K. by 1992, with similar evidence obtained from the FDA, 
no such adverse effects were noted in the short term BCPT. 
	NCI's preliminary April 6 report on the prevention 
of breast cancer by tamoxifen has still not been finalized 
and published in a scientific journal.  The advisory 
committee should consider the propriety of Zeneca's NDA 
submission as it is based, in part, on data which have not 
been made fully available to the public although the 
underlying NCI research was funded by the public.  
Furthermore, the claimed evidence for chemoprevention has 
been rebutted by two subsequent scientific publications.  Of 
as great concern is the well-documented evidence of 
short-term life-threatening complications, and also risks of 
delayed fatal complications, evidence for which has been 
trivialized and suppressed by NCI.  Based on these 
scientific and ethical considerations, the advisory 
committee is urged to deny approval of Zeneca's NDA. 
	This and the other letters are available for your 
viewing at the registration table outside. 
	Our second letter is by Barbara Brenner of Breast 
Cancer Action.  It says:  Dear Committee Members, based on 
the data currently available, both from the NCI and from the 
recently released European results, Breast Cancer Action 
opposes approval of the proposed indication for Nolvadex.  
Women are entitled to expect that any drug approved for the 
prevention of breast cancer will both actually prevent the 
disease and carry benefits that outweigh the risks of taking 
it.  As far as we know now, neither is true for Nolvadex.  
We urge you to "just say no" to this application.
	Breast Cancer Action is an education and advocacy 
organization founded and led by women living with breast 
cancer, representing over 4000 members throughout the United 
States and beyond, we carry the voices of people affected by 
breast cancer to inspire and compel the changes necessary to 
end the breast cancer epidemic.  Since our founding in 1990, 
we have been calling for research into true breast cancer 
prevention, as well as research on effective treatments.
	The history of the breast cancer prevention trial 
that led to the application that is now before the committee 
is well known.  Breast Cancer Action long ago summarized the 
trials as "bad research, bad drug, bad news for women."  But 
it is not the history of the trial that concerns us today; 
it is the current state of information about the drug's 
preventive effects and the risks associated with its use.
	The data currently available regarding the use of 
tamoxifen in healthy women point to far too many known and 
unknown risks to justify the approval of Nolvadex as a 
preventive.  The risks, as revealed by the BCPT-1 data, are 
presumably well known to the FDA and the committee.  But 
seeing them listed gives us and, hopefully, the committee 
members the overwhelming sense that this application is 
premature in the extreme. 
	From studies of tamoxifen in women with breast 
cancer and from the BCPT-1 trial, some of the side effects 
of taking tamoxifen are known:  Endometrial cancer, 
pulmonary embolism, deep vein thrombosis, eye damage, 
depression, irritability, vaginal dryness, hot flashes, 
memory loss and weight gain. 
	Because BCPT-1 ended before the 5 years for which 
the trial was designed, because a number of the participants 
were involved in the trial for far less than 4 years, and 
because there is no rigorous follow-up guaranteed for the 
trial participants, there is much we do not know about the 
consequences of tamoxifen for healthy women at high risk for 
breast cancer.  Given the recruitment of BCPT-1 participants 
into the STAR trial, BCPT-2, even the minimal follow-up 
planned for BCPT-1 participants will be of little or no 
value in resolving the many unknowns about tamoxifen.  Among 
the most troubling unknowns are these:
	Long-term effects of the drug in terms of breast 
cancer risk or any other risk; appropriate duration of 
treatment; how long the protective effect of the drug lasts; 
whether and how benefits and risks vary depending on the 
race/ethnicity of the woman taking the drug; whether and how 
benefits and risks vary depending on age of the woman taking 
the drug; whether and how benefits and risks vary depending 
on breast cancer risk factors; and whether women who develop 
breast cancer while on tamoxifen develop a more aggressive 
form of the disease.
	While it will be argued that some of the foregoing 
information is known, we disagree.  Either because of the 
trial design or because data about the trial has not been 
made available before now, we simply do not have the answers 
to these questions.  All of these concerns are addressed at 
length in the lead article in the June/July, 1998 edition of 
the "Breast Cancer Action Newsletter," a copy of which is 
attached to this testimony for the committee's convenience.
	Last but certainly not least, the data that are 
currently available clearly indicate that, whatever else 
tamoxifen does for healthy women, it does not prevent breast 
cancer.  The BCPT-1 data show only that for some small group 
of women the drug may delay the onset of the disease.  The 
NCI's conclusions, even in this regard, are undermined by 
the recently released European results finding no benefit 
from tamoxifen in healthy women at high risk. 
	Whatever else is true, if someone taking Nolvadex 
can develop breast cancer, then the drug is clearly not 
preventing the disease in any sense that the general public 
understands.  What epidemiologists mean by prevention is not 
what people who are worried about breast cancer mean when 
they use or, more importantly, hear the word.
	When we finally have a drug that we know will 
reduce a woman's risk of developing breast cancer, with 
attendant risks of side effects that are both known and 
acceptable, we will encourage this committee and the FDA to 
approve it under an indication of "risk reduction," not 
"prevention."
	But, as far as we know today, Nolvadex is not that 
drug.  For this committee to approve the indication that 
Zeneca is now requesting would expose millions of healthy 
women to the known risks of tamoxifen and to potentially 
grave unknown risks without any guarantee of obtaining the 
benefits that are being claimed.  Only one word can 
accurately describe such an action -- unconscionable.  Do 
not let Zeneca's drive for profit divert you from the 
interests of women at high risk for breast cancer. 
	Respectfully submitted by Barbara A. Brenner, 
Executive Director. 
	As a matter of policy, in order to avoid the fact 
or appearance of a conflict of interest, Breast Cancer 
Action does not accept funding from Zeneca or from any other 
pharmaceutical company. 
	Thank you and, again, both letters are available 
for you to look at, at the registration desk.
	DR. DUTCHER:  Since we do have time later in the 
morning for other comments and people are scheduled to 
speak, we are going to proceed with the agenda as it is 
printed and we will begin with the sponsor's presentation.
Sponsor Presentation
Introduction
	DR. LEWIS:  Thank you, Dr. Dutcher.  Good morning.  
I am Jerry Lewis, Senior Medical Director of Zeneca 
Pharmaceuticals, responsible for Nolvadex, tamoxifen 
citrate. 
	[Slide]
	I have the distinct pleasure today of representing 
Zeneca, and along with my colleagues from the NSABP, the 
National Cancer Institute and the FDA, we will present and 
discuss with you the results of the precedent-setting breast 
cancer prevention trial. 
	This is the basis for Zeneca's supplemental NDA 
for a change in the labeling -- Nolvadex is indicated for 
the prevention of breast cancer in women at high risk for 
developing the disease. 
	[Slide]
	Following my introductory comments, Dr. Jo 
Costantino, from NSABP, will present the summary of the 
breast cancer prevention trial results.  At the conclusion 
of Jo's presentation, I will summarize Zeneca's position and 
then be pleased to take questions from the committee.
	[Slide]
	There are a number of experts here with us today 
to help address your questions.  From NSABP, Dr. Norman 
Wolmark, Principal Investigator and Chairperson of NSABP; 
Dr. Costantino, and Dr. Larry Wickerham, Director of 
Operations at NSABP.  For the National Cancer Institute, Dr. 
Leslie Ford, Associate Director, Early Detection and 
Community Oncology Program; and from Zeneca there are a 
number of scientists that are available should they be 
needed. 
	[Slide]
	Zeneca is very proud that NSABP selected tamoxifen 
to be evaluated in the breast cancer prevention trial.  
NSABP has been involved in cancer research for some 40 
years, and has been studying tamoxifen for some 20 years. 
	In 1991, the NSABP met with the predecessor ODAC 
to discuss the breast cancer prevention trial.  We have with 
us today here Dr. Bernie Fisher who participated in those 
deliberations.  The ODAC at that point endorsed the trial 
after they were convinced that the potential benefits 
outweighed the known risks.  The trial was designed to 
detect a reduction in breast cancer risk of 33 percent in 
women at high risk. 
	[Slide]
	The trial itself far exceeded these expectations.  
Tamoxifen for 5 years prevented 45 percent of invasive 
breast cancers in women at high risk, and no unanticipated 
toxicities occurred in the trial.  For a drug with 10 
million patient years of exposure, confirmation of the 
safety data base should not comes as a surprise. 
	Today is a milestone for it represents the first 
time that the advisory committee is gathered to deliberate 
and vote on a drug for breast cancer prevention and, indeed, 
for any drug for prevention of cancer.  Reaching this point 
in the review process as quickly as we have has been 
accomplished by tremendous cooperation between NSABP, the 
NCI and the FDA. 
	[Slide]
	Let me review this time-line for you.  The results 
of the breast cancer prevention trial were made known to 
investigators and, indeed, the world on April 8 of this 
year.  Some 22 days later Zeneca filed a supplemental new 
drug application and the FDA granted it an accelerated 
review.  And, here we are today, a mere 5 months later, on 
September 2, to consider the results of this trial and a 
label change for Nolvadex. 
	[Slide]
	It now gives me great pleasure to introduce Dr. Jo 
Costantino, Associate Director, NSABP, who will present the 
data from this trial.  These data support our new 
indication.  Thank you very much.  Jo?
Summary of the Breast Cancer Prevention Trial Results
	DR. COSTANTINO:  Thank you, Dr. Lewis. 
	I am pleased to be here this morning to have the 
opportunity to provide for you the results of the breast 
cancer prevention trial. 
	[Slide]
	I would like to begin just by answering the 
question why tamoxifen?  Why did NASBP choose tamoxifen to 
be the drug to evaluate as a preventive agent for breast 
cancer?  Primarily because of three factors. 
	First of all, the drug has been proven to be 
beneficial in the treatment of breast cancer in both 
advanced and early stage disease.  It was also shown to 
lower the risk of contralateral breast cancer among those 
patients.  And, there was preclinical evidence demonstrating 
that tamoxifen inhibits the growth of tumors, and perhaps 
does this by interfering with both the promotion and 
initiation mechanisms.
	[Slide]
	The breast cancer prevention trial was a 
double-blinded, randomized clinical trial in which women 
were randomized to receive the planned duration of 5 years 
of tamoxifen or 5 years of placebo, and 13,388 women were 
actually randomized to the trial. 
	[Slide]
	The primary objective of the study was to evaluate 
the effect of tamoxifen on the reduction of the incidence of 
invasive breast cancer.  The study was powered to determine 
that endpoint. 
	[Slide]
	Other objectives included the evaluation of the 
effect of tamoxifen on cardiovascular disease, bone 
fractures, other cancers, mortality and the risks of some 
other outcomes which were known to be risk factors 
associated with tamoxifen that we had learned from the 
treatment trials. 
	[Slide]
	The study was designed to maintain the statistical 
power even if the non-compliance was as high as 10 percent 
per year.  This is an important factor because this is 
something that we had planned for in advance.  We 
anticipated there might be a large non-compliance and we 
wanted to make sure that we did not reduce our statistical 
power if there was such a fact. 
	The analysis was based on an intent-to-treat 
approach.  That indicates that all individuals were included 
in the treatment arm that they were assigned and that all 
events were included regardless of whether or not they took 
the drug. 
	[Slide]
	Women got into the trial based on eligibility 
criteria, one of which was being at high risk for breast 
cancer.  High risk was defined in this trial as being at 
least 60 years of age, being age 35 or older and having a 
history of lobular carcinoma in situ, or being greater than 
age 35 and having a 5-year absolute risk of breast cancer 
that was equivalent to the 60-year old woman, and that 
absolute risk was defined as 1.66 percent in 5 years. 
	The determination of this breast cancer risk was 
based on a mathematical model developed by Dr. Mitchell Gail 
and his associates at the National Cancer Institute. 
	[Slide]
	The factors that went into that model that helped 
to determine what the risk of breast cancer was for each of 
these women included age, first degree relatives with breast 
cancer, parity and age at first live birth, number of breast 
biopsies, history of atypical hyperplasia, age at menarche 
and race. 
	The original Gail model only incorporated this 
first set of parameters.  It did not include a factor for 
race.  But we worked with Dr. Gail and we developed a factor 
to include race into the program so that we could also 
calculate predictive risk for non-white women. 
	[Slide]
	In addition, the original implementation of the 
Gail model was designed to predict the risk of both invasive 
and non-invasive breast cancer.  In the BCPT we were 
interested in just predicting the incidence of invasive 
breast cancer so we made modifications to account for that 
also. 
	Almost 100,000 women had their breast cancer risk 
assessments performed.  Of those 98,000, approximately 
57,500 women were eligible based on that 1.66 percent in 5 
years.  Now, among those women who were eligible, there were 
other medical eligibility criteria that had to be met.  If a 
woman desired to be considered for randomization, she went 
on to be screened and ultimately 13,388 women were 
randomized. 
	The data that I am going to present to you today 
is based on the follow-up as of January 31, 1998.  This was 
the data that was actually used by our data monitoring 
committee when they decided that the trial had met its 
objectives and that the trial should be disclosed. 
	As of that date, January 31, 1998, follow-up was 
available for 13,114 women, and the average follow-up time 
was 44 months.  About 73 percent of the women at that time 
had been followed for more than 3 years.  Almost 60 percent 
had been followed for more than 4 years, and 21 percent had 
been followed for 5 or more years. 
	[Slide]
	I would like to start just by quickly reviewing 
some of the baseline characteristics related to risk that 
the population had.
	[Slide]
	I will begin with age, and 39 percent of the women 
were in the age range of 35 to 49 at the time they were 
randomized; 31 percent were in the age range of 50 to 59; 
and 30 percent were 60 years of age or older. 
	[Slide]
	In terms of number of relatives with a history of 
breast cancer, 57 percent of the population had at least 1 
relative with a history of breast cancer; 16 percent had a 
history of 2 relatives with a history of breast cancer; and 
3 percent had a history with 3 or more relatives with breast 
cancer.
	[Slide]
	In terms of the 5-year absolute breast cancer risk 
predicted from the Gail model, 25 percent of the women had a 
risk of less than 2 percent in 5 years; 31 percent had a 
risk in the range of 2-3 percent at 5 years; and 17 percent 
had a risk of 5 or more in 5 years. 
	[Slide]
	A significant number of women entered into the 
trial with a history of LCIS and a history of atypical 
hyperplasia.  Over 800 women in the trial, about 6.2 
percent, entered the trial reporting a history of lobular 
carcinoma in situ and about 9.2 percent, approximately 1200 
women entered into the trial with a history of atypical 
hyperplasia. 
	[Slide]
	Now I would like to begin with the results, the 
primary endpoint of invasive breast cancer.
	[Slide]
	This plot is a plot of the cumulative incidence of 
invasive breast cancer that occurred among the participants 
in the trial.  The black line represents the cumulative 
incidence for the placebo group.  The red line represents 
the cumulative incidence for the tamoxifen group.
	As you can see, the cumulative incidence for the 
placebo group was substantially greater than it was in the 
tamoxifen group.  In fact, there were 154 breast cancers 
which occurred in the placebo group compared to only 85 in 
the tamoxifen group.  This represents a cumulative incidence 
of 32/1000 compared to 17.9/1000, representing a reduction 
of about 45 percent in the risk of breast cancer.  This 
difference was highly statistically significant with the p 
value being less than 0.00001.
	A couple of things to note in this plot are that 
the difference appears to show itself very early on, and it 
does sustain itself throughout the whole 5 years of the 
plot. 
	[Slide]
	Similar findings are noted for non-invasive breast 
cancer.  This is the same type of plot only now we are 
dealing with non-invasive breast cancer.  In the placebo 
group there were 59 events of non-invasive breast cancer 
compared to 31 in the tamoxifen group.  This equates to a 
cumulative incidence of 12.3/1000 in the placebo compared to 
6.8 in the tamoxifen group.  This represents a 47 percent 
reduction in the risk of breast cancer.  Again, you can see 
that the curves separate rather early, before the first 
year, and they continue to separate through the entire 
duration.
	[Slide]
	This slide reiterates the fact that this finding 
is consistent across time and has a lasting effect.  These 
are bar charts, and the heights of the bars represent the 
rate per 1000 of invasive breast cancer by each of the years 
of follow-up.  So you can understand the number of events 
that went into calculating these rates, at the top of the 
bars the numbers are given and these represent the number of 
cases.  The yellow bars represent the rate in the placebo 
group; the red bars, the rate in the tamoxifen group. 
	If you look across all the years, all the way 
through year 5, you see there is a substantial reduction in 
the risk of breast cancer all the way up to year 5 and even 
a 50 percent reduction is evident at year 5. 
	[Slide]
	To give you a feel for how things look by some of 
the characteristics of the population, here is the rate of 
invasive breast cancer broken down by 3 age groups -- less 
than 49, 50 to 59, and 60-plus.  Again, you can see in all 3 
age groups that there is a substantial reduction of the rate 
of invasive cancer in the tamoxifen group. 
	[Slide]
	Here we show the rates broken down by those who 
reported a history of lobular carcinoma in situ and those 
with a history of atypical hyperplasia.  Again, there are 
striking reductions in both of these populations.
	[Slide]
	This chart shows the rates comparing treatment 
groups by categories of predicted risk from the Gail model, 
less than 2, 2-3, 3-5 and greater than 5.  Again comparing 
each of these categories, you can see that there is a 
substantial reduction in the tamoxifen group, and this 
magnitude of reduction, seen here at the upper group, is 
about the same in terms of relative risk as it is in the 
lower group.  Statistically speaking, there was no 
significant difference between the reduction observed across 
any of the categories of risk. 
	[Slide]
	I would like to take a few minutes now to describe 
to you some of the tumor characteristics of the cases that 
were diagnosed in the trial and how they compared by 
treatment arm.
	[Slide]
	The first slide deals with tumor size.  What we 
have here is the rate of invasive cancer by the size of the 
tumor at the time it was diagnosed, those that are less than 
1 cm, 1-2 cm, 2-3 cm, and greater than 3 cm.  Again, 
comparing the bars or comparing placebo to tamoxifen, you 
can see that there is a reduction in all categories but the 
bulk of the reduction, the most significant reduction was 
among tumors that were less than 2 cm in size. 
	[Slide]
	This graph shows the rates by categories of nodal 
status, those who were diagnosed with no positive nodes, 
those who were diagnosed with 1-3, and those who were 
diagnosed with 4 or more nodes.  You will note that there is 
a really high number of unknowns here, and this is because 
the majority of these women did not have axillary dissection 
so the status is in terms of nodes that could not be 
determined. 
	If you look at the data, again, there is a 
striking reduction for those who were diagnosed with no 
nodes, and also those who were diagnosed with 1-3, but there 
is no difference in the rates of cancer for those who were 
diagnosed with 4 or more nodes.  This is important to note 
at this point -- tamoxifen is reducing the rates of disease 
associated with 1-3 nodes and no nodes; there is no increase 
in the number of cases being detected with 4 or more nodes; 
and there is no increase in the number of cases being 
detected that are larger tumor size.  It appears that 
tamoxifen is culling out the smaller tumors and the tumors 
that present with less than 4 nodes.  So, the theory that 
cases that occur on tamoxifen are more aggressive is not 
being demonstrated by the data. 
	[Slide]
	The last tumor characteristic is ER status, and 
this is an important one because there is an interaction 
between ER status and the effect of tamoxifen.  These two 
bars represent women who were diagnosed with tumors that 
were ER positive.  You see a very striking reduction in the 
risk of cancer based on those who were ER positive.  On the 
other hand, there was no difference in the rates of women 
who were diagnosed with tumors that were ER negative.  So, 
the effect of tamoxifen appears to be affecting tumors that 
would present themselves as being ER positive. 
	[Slide]
	To summarize the findings in terms of breast 
cancer, tamoxifen reduced the incidence of invasive breast 
cancer by 45 percent.  Reduction is seen in women of all age 
groups and at all levels of breast cancer risk.  And, 
tamoxifen also reduced the incidence of non-invasive breast 
cancer.
	[Slide]
	I would now like to turn to other cancers that 
were diagnosed in the trial, starting with endometrial 
cancer.  When we began the trial we were aware that 
endometrial cancer was a potential risk for women who were 
using tamoxifen.  Indeed, from the world's literature 
involving treatment trials, we estimated that the risk of 
endometrial cancer might be elevated about 2-3 fold overall 
in the population.  Indeed, that is exactly what we found in 
the prevention study.
	In the placebo group there were 14 cases of 
endometrial cancer diagnosed compared to 33 cases in the 
tamoxifen arm, for a relative risk of about 2.5.  When this 
was broken down by age group, there was really no difference 
evident at this time between the treatment groups for women 
who were less than 49 years of age at the time they entered 
the trial.  On the other hand, for women who were greater 
than 50 years of age when they entered the trial there was a 
substantial difference, 6 versus 26 cases. 
	[Slide]
	It is important to note that all except for 1 of 
the cases in the trial were diagnosed at an early stage.  
All of them were FIGO stage I, 13 on placebo and 33 in the 
tamoxifen group.  There was 1 case that was a stage IV, and 
this occurred in the placebo group. 
	It is also important to note that most of these 
cases were picked up by a mechanism which included annual 
pelvic exams and every 6 months a questioning of the 
individuals regarding gynecologic symptoms, and stressing to 
the individuals that whenever gynecologic symptoms occur 
they should report them immediately and have them followed 
up. 
	About 3 or 4 years into the trial, in 1995 
actually, NSABP began paying for women who wished to have 
endometrial biopsies as part of their follow-up every 6 
months on the trial.  Some of the women did participate in 
that. 
	[Slide]
	Only about half of the women in the trial who were 
eligible for screening -- and when we say eligible now, we 
are talking about women who actually have uteri, and I might 
add that all the rates that we are talking about here for 
endometrial cancer are based only on women who are at risk, 
women who had a uterus.  About 37 percent of the women who 
came into the trial, at the time of randomization had a 
hysterectomy. 
	So, 67 percent of the women in the trial were at 
risk for endometrial cancer, and when we calculated these 
rates these were based only on women at risk.  That is why 
you see on the bottom line that a little over 4000 women in 
each arm were at risk.  This group of women actually 
participated in endometrial sampling; this group did not.  
This is the breakdown of the total number of cancers that 
were detected among the group who were sampled and the group 
who were not sampled. 
	As you can see, the rate of detection of cancer 
was not statistically significantly different, 0.6 percent 
in those who were sampled compared to 0.5 percent in those 
who were not sampled. 
	[Slide]
	To summarize the conclusions in terms of 
endometrial cancer then, tamoxifen increases the risk of 
endometrial cancer.  Annual pelvic exams, directed 
questioning regarding gynecologic problems and the prompt 
reporting and evaluation of symptoms can be successfully 
used to detect endometrial cancer in early stage.  The use 
of endometrial biopsy did not significantly improve the rate 
of cancer detection, and the small difference in detection 
does not justify the use of endometrial biopsy as a 
screening method. 
	Consistent with these findings, when we are 
planning our next prevention study we are not recommending 
that endometrial biopsy be included as part of the routine 
follow-up.
	[Slide]
	Turning now to other cancers, cancers other than 
the breast and cancers other than endometrial, this table 
summarizes the complete experience of the trial.  Overall, 
there were 88 other cancers in the placebo group compared to 
85 in the tamoxifen group.  You can see here the 
distribution by all the different cancers.
	It is important to note a few of these because 
some of these were suspected as being possibly associated 
with tamoxifen and it turns out that they were not.  There 
is no difference in colon cancer.  No difference in rectal 
cancer.  No liver cancers.  In fact, there is no difference 
in any cancer at all as you look down the list. 
	[Slide]
	Ischemic heart disease was included in the trial 
because it was known that tamoxifen reduces levels of lipids 
and perhaps that would result in a reduction in the risk of 
heart disease.  There were actually 4 different specific 
ischemic events that were included as endpoints in the 
trial.  These included fatal myocardial infarction; 
non-fatal myocardial infarction; a category of illness we 
called severe angina, and that was defined as having angina 
that required angioplasty or coronary bypass surgery; and 
the last endpoint that was included was called acute 
ischemic syndrome, and this included individuals who had 
changes on the ECG but not necessarily elevated enzymes or 
chest pain, or individuals who had severe chest pain and 
required hospitalization but did not have to have surgery. 
	This table shows the results from those endpoints.  
First of all, overall there were 59 ischemic events in the 
placebo group compared to 61 in the tamoxifen group.  
Dealing with just the myocardial infarctions, there were 27 
in each arm.  If you were to cull out those that were fatal 
MIs, the numbers would be 8 versus 7.  In terms of the 
severe angina, those requiring bypass or angioplasty, 12 and 
12 -- the same number in each arm.  In terms of acute 
ischemic syndrome, the numbers were also the same, 20 and 
22.  So, at this time the results of the trial do not 
support the contention that tamoxifen does reduce the risk 
of ischemic heart disease. 
	[Slide]
	Fracture events -- fractures were included as a 
possible endpoint because of the estrogenic effect of 
tamoxifen thought to be preserving bone.  To evaluate this 
we included 3 specific endpoints of fractures that we 
identified a priori which we thought were fractures that 
would be more likely to represent osteoporotic type of 
fractures.  Those 3 endpoints included fractures of the hip, 
fractures of the spine and fractures of the lower radial 
called Colles' fractures. 
	Overall, there were 61 of these type fractures in 
the placebo group compared to 33 in the tamoxifen group, for 
a reduction of about 46 percent overall of these types of 
fractures.  Looking specifically at the types of fractures 
that occurred, hip fractures were 20 versus 9; Colles' 
fractures were 12 versus 7; and spine fractures were 30 
versus 19.  These numbers don't add up exactly to 61 and 33 
because there is 1 woman here who had a hip and a wrist 
fracture.  There are 2 women here.  One had a hip and spine 
and one had a hip and wrist fracture, and they are counted 
individually in that level. 
	[Slide]
	Vascular events -- as I indicated before, in 
addition to endometrial cancer we were also aware that there 
were other potential risks associated with tamoxifen.  We 
learned this from the extensive history that we had with 
treatment trials.  These included thromboembolic events such 
as pulmonary embolism and deep vein thrombosis. 
	This bar chart shows the distribution of rates and 
the number of events occurring for pulmonary embolism, deep 
vein thrombosis, stroke and transient ischemic attack.  In 
terms of pulmonary embolism, there were 6 cases in the 
placebo compared to 18 cases in the tamoxifen arm.  Three of 
the cases in the tamoxifen arm resulted in death, and this 
difference was statistically significant.
	In terms of deep vein thrombosis, there were 19 
events in the placebo arm compared to 30 events in the 
tamoxifen arm.  This difference was not statistically 
significant.
	In terms of stroke, there were 24 in the placebo 
compared to 34 in the tamoxifen arm.  Again, this difference 
was not statistically significant, and there really was no 
difference between the 2 arms in terms of transient ischemic 
attack. 
	[Slide]
	Ophthalmic events -- when we planned the study 
there were also reports in the literature suggesting that 
tamoxifen might have some impact on visual effects.  For 
that reason, we did two things.  First, we undertook a 
special study in one of our that trials, NSABP-14 and, 
secondly, we included questions in follow-up information in 
the P-1 trial to help us understand and collect information 
regarding the occurrence of eye toxicities,
	In terms of the NASBP-14 trial, approximately 300 
women were called in and participated in very extensive eye 
examinations to determine if there were problems.  The 
results of that study indicated that there were no problems 
with the development of retinal crystals -- retinal crystals 
is one of the things which was theorized to be one of the 
potential side effects.  There also were no problems with 
macular edema or macular degeneration.  However, the results 
from the study suggested that there might be a problem with 
cataracts. 
	[Slide]
	In the prevention study we also found that there 
was no relationship between macular degeneration and 
exposure to tamoxifen.  The actual number of events and the 
rates were identical between the 2 arms.  On the other hand, 
we did find that there was a difference in the rates of 
cataracts. 
	Of 483 women who came into the trial in the 
placebo arm without cataracts, developed them during the 
course of the trial compared to 540 in the tamoxifen arm.  
This represents about a 13 percent increase in the risk of 
developing cataracts.  Among those women who developed 
cataracts, 63 out of the 483 went on to have cataract 
surgery compared to 101 out of the 540 in the tamoxifen arm.  
This represented about a 60 percent increase in the risk of 
having cataract surgery. 
	[Slide]
	The next item I would like to talk about is total 
deaths.  Overall, there were 65 deaths in the placebo group 
compared to 53 in the tamoxifen arm, 5 of the deaths in the 
placebo group were due to breast cancer compared to 3 in the 
tamoxifen arm. 
	There was 1 endometrial cancer death.  This 
occurred in the placebo group, and was diagnosed with a FIGO 
stage IV endometrial cancer. 
	In terms of heart disease -- all heart disease not 
just ischemic, ischemic was 8 versus 7; total heart disease 
is 12 versus 12.  Stroke was 3 versus 4.  As I mentioned 
already, there were 3 deaths due to pulmonary embolism in 
the tamoxifen arm, and so on and so forth.
	If you look down at every single cause, and there 
are many causes in here, there are no differences between 
any cause of death between the arms. 
	[Slide]
	To summarize the findings from the BCPT, first of 
all, tamoxifen use prevents invasive breast cancer among 
women in all age groups and at all levels of predicted 
breast cancer risk, and a similar effect is evident for the 
prevention of non-invasive breast cancer.
	[Slide]
	Rates of osteoporotic fractures were lower in the 
women in the tamoxifen group.  The risks of tamoxifen 
include endometrial cancer, thromboembolic events and 
cataracts.  No difference between the that groups was noted 
for rates of heart disease, other cancers, macular 
degeneration or other vision conditions affecting permanent 
vision loss. 
	[Slide]
	Our conclusions then are that the BCPT was 
designed as the definitive trial to test the hypothesis that 
tamoxifen use would reduce the risk of breast cancer.  The 
findings indicate that tamoxifen use can significantly 
reduce the risk of both invasive and non-invasive disease.
	[Slide]
	The weight of evidence from the trial is 
substantial in comparison to the recently published 
preliminary findings of the 2 smaller and differently 
designed European studies.  Thus, we conclude that women who 
are at high risk, as defined in the BCPT, should be 
considered as candidates for the use of tamoxifen to prevent 
breast cancer. 
Summary
	DR. LEWIS:  Thank you very much, Jo.  Before we 
open the meeting to questions, I would like to summarize 
Zeneca's position on Nolvadex in prevention.
	[Slide]
	Tamoxifen, as given in the breast cancer 
prevention trial, prevents 45 percent of invasive breast 
cancers in women at high risk.  Benefit was seen in all age 
groups and at all levels of risk.  The safety was as 
anticipated from earlier trials, and is covered in our 
current label.  The definition of who is at high risk is as 
described in the label and in the trial.  This information 
has been incorporated into our current label. 
	Having identified a woman who is at high risk of 
breast cancer, it is appropriate for that woman to have 
discussion with her health care provider to determine if 
tamoxifen is right for her.  This discussion should include 
the necessity for medical care follow-up because tamoxifen 
is not a substitute for good medical care but an addition to 
it. 
	[Slide]
	It is our believe that good medical care for all 
women includes regular examinations, mammography and pelvic 
examinations, and follow-up of any abnormal signs and 
symptoms. 
	[Slide]
	Finally, we believe these data support our claim 
that tamoxifen is indicated for the prevention of breast 
cancer in women at high risk for developing the disease. 
	Thank you very much for your attention, and I 
would be pleased to take questions from the committee.
Questions from the Committee
	DR. DUTCHER:  The company has given us half of 
their time to ask questions of them.  So, we appreciate 
that.  Dr. Albain?
	DR. ALBAIN:  Thank you, Dr. Dutcher.  I think it 
goes without saying that we congratulate the sponsor and 
NSABP for conducting this landmark trial. 
	It struck me in the data again, presented this 
morning, about the courage of the over 13,000 women who 
consented to randomization in this trial, as well as the 
extensive support this trial received from the start from 
the lay advocacy community and breast cancer survivors.  
With that as an opening statement, I would like to take the 
discussion right away to one of the major topics of 
discussion out there since the data was released in May at 
the ASCO meetings, and that is the admittedly short 
follow-up at this stage for the endpoint of preventing 
cancers.
	I was wondering if you or NSABP could comment on 
some of the data that is out there that has much longer 
follow-up, those breast cancer survivors who received 
tamoxifen for an adjuvant therapy indication, who have now 
been followed much, much longer than NSABP-14 or perhaps the 
worldwide overview data that supports a 45-50 percent 
reduction in risk of second cancers.  Is the maturity of 
that data in any way supportive of this particular 
indication? 
	DR. LEWIS:  I would like to call on Dr. Wolmark to 
make some comments on the NSABP trial itself.
	DR. WOLMARK:  Thank you.  I would like to echo 
your remarks on acknowledging the role of the 13,388 
participants in this trial, without whose courage and 
perseverance and dedication and selflessness we would not be 
here today. 
	Relative to your questions as far as the mean time 
on study and the duration of the effect of tamoxifen, Dr. 
Costantino showed you the reduction in relative risk over 
the period of years of follow-up, and that reduction was 
durable throughout the five years and now into the sixth 
year.  So, even beyond the discontinuation of tamoxifen we 
still see a reduction.
	Relative to the data from B-14 where we used the 
contralateral breast as a surrogate marker for prevention, 
there too we see that the effect is not a transient one but 
durable.  Those differences that were noted at five years 
were still very much apparent at ten years of follow-up.  
That is also true for cumulative analyses of all the NSABP 
trials relative to the contralateral breast, and is entirely 
consistent with the overview analysis relative to the 
contralateral breast, indicating that this is not a 
transient effect but a durable one.
	DR. ALBAIN:  To follow that up, what are the 
confidence intervals like out at the 4- and 5-year parts of 
your annual hazard curve that you showed and just alluded 
to?  We didn't see those on the slide.
	DR. WOLMARK:  Yes, confidence intervals are a 
reflex response for me to call upon the statistician.
	[Laughter]
	So, perhaps Dr. Costantino would like to look up 
the confidence intervals to precisely address your question, 
and perhaps you might have another one as he is looking 
those up. 
	DR. ALBAIN:  I have the same question for the 
reduction in risk of invasive cancers by your predefined 
risk strata by risk. 
	DR. COSTANTINO:  I don't have the exact confidence 
limits here with me, but I can tell you that --
	DR. WOLMARK:  It was an excellent question 
nonetheless!
	[Laughter]
	DR. COSTANTINO:  -- that the relative risk was 
about 50 percent.  The confidence limits for that individual 
year approached statistical significance.  But there was no 
indication that there was a difference in the hazard rate 
over time.  I think that is the more important question, 
were the hazard rates constant over time?  And, all the data 
that we have analyzed, including some of the data that was 
done independently by the FDA, indicate that the hazards are 
constant over time.  So, there is no suggestion that there 
might be differences over time. 
	DR. ALBAIN:  And what were those generally, those 
hazards?
	DR. COSTANTINO:  Well, about 6/1000 is what it is 
in the placebo group and about 3.4/1000 in the tamoxifen 
group.
	DR. ALBAIN:  Thank you. 
	DR. DUTCHER:  Dr. Sledge?
	DR. SLEDGE:  I have several questions I want to 
ask.  If one looks at the hazard rates for endometrial 
cancer -- I would echo my esteemed colleagues on what a 
wonderful study this is in terms of its design and 
development, but I will tell you, as a practicing medical 
oncologist who takes care of breast cancer patients, I 
pretty much felt I knew the answer before the study was 
started in terms of a chemoprevention effect.  I think many 
of us who have worked in this field for many years felt that 
tamoxifen was a chemopreventive drug before the trial was 
ever started.  So, this primarily comes down to the 
risk-benefit questions rather than the true scientific 
question of whether or not it can prevent breast cancer.
	If you allow for that, I think a number of 
important questions come up.  Let's start with the 
endometrial cancer question.  If I am reading the numbers 
correctly, 37 percent of the women had a prior hysterectomy 
and 31 percent of the women were premenopausal.  The figures 
that we were given in terms of hazard rates are hazard rates 
for the general population of women in the trial but, of 
course, if I go out to the clinic next week with a woman who 
is postmenopausal with a uterus, the general hazard rate 
from the trial is pretty useless in terms of me speaking to 
that patient.  So, what is the hazard rate for a 
postmenopausal woman who has an intact uterus of getting 
endometrial cancer in any given year? 
	DR. COSTANTINO:  Actually, I did indicate that 
these are the hazard rates based on women with uterus 
according to their age.  So, these hazard rates you see are 
exactly what you are asking for.  So, it is 3.21/1000 women 
who have a uterus.
	DR. SLEDGE:  Postmenopausal?
	DR. COSTANTINO:  Over age 50 or under age 50.  We 
used age here as a categorization for menopausal status, as 
an approximation. 
	DR. SLEDGE:  Okay, thank you.  The second question 
again relates to the question of risk.  The proposed 
indication is for women with the risk of a 60-year old and, 
yet, the average risk of the women entering the trial was 
considerably higher.  Since this is largely a risk-benefit 
issue, what do we say to a woman who doesn't have quite as 
high a risk as the woman who entered the trial in terms of 
whether she should go on tamoxifen or not?  I looked in the 
package insert, and the package insert basically says women 
went into the trial based on the Gail model.  It gives us a 
number of scenarios in terms of who should be considered for 
tamoxifen, and then after all the scenarios are given it 
says that these scenarios only account for 17 percent of the 
women who went into the trial.  How is the average general 
internist or OB-GYN out in the community supposed to decide 
who is going to go onto this trial?
	DR. WOLMARK:  Well, I think obviously the 
information presented today is only relevant for those 
individuals who met the criteria of increased risk as 
defined by the BCPT which was, in turn, a modification of 
the Gail model.  I think it is incumbent on us to define 
whether that individual is, in fact, at increased risk and 
meets the eligibility criteria for entry into the BCPT 
protocol.
	There have been a number of actions that have been 
taken to widely disseminate this information, to make it 
user-friendly, and also to be readily available to both the 
physician or to the individual who is considering the use of 
tamoxifen.  Perhaps Dr. Leslie Ford could comment on what 
these efforts have been up to this point. 
	DR. FORD:  The NCI has obviously been very 
interested in the issue of how we communicate breast cancer 
risk to women, both in the context of this trial and in 
other work that we do.  One of the things that we have been 
working on since the April announcement has been a 
user-friendly way of assessing a woman's risk of developing 
breast cancer based on the Gail model, and it has gone 
through some very early data testing but we are about to 
start distributing what we call our breast cancer risk 
assessment tool.  It is available by request through our 
cancer trials web site. 
	We will also be sending copies to the major 
medical societies, and announcing its availability in the 
newsletters of the major advocacy organizations and medical 
societies for distribution.  The NSABP will also be 
distributing these risk assessment tools so women and their 
physicians can, in a sense, plug in their risk factors and 
determine what their 5-year time risk is of developing 
breast cancer and whether it was similar to the women that 
participated in the study.
	DR. SLEDGE:  I think that is absolutely crucial 
for a drug like this because I can tell you, looking at the 
package insert, it is definitely not user-friendly in terms 
of trying to determine --
	DR. WOLMARK:  Is there a package insert that is?
	[Laughter]
	DR. SLEDGE:  I think most package inserts are 
pretty simple.  I think for this drug, if we are talking 
about adjuvant therapy for breast cancer, it would be a lot 
easier to describe. 
	DR. HONIG:  May I make a comment?  I would just 
add also that in addition to those tables of risk that are 
in the label as it stands now, if you add in the other 
categories such as preceding diagnosis of LCIS or age, it 
actually accounts for a little over 50 percent of the 
profiles of the women who went on the study.  It is not 100 
percent, obviously, but it is a little over half.
	DR. SLEDGE:  And that is not clear in the package 
insert.  If I am reading the results correctly, tamoxifen is 
not eliminating the largest tumors; it is not eliminating 
the most node-positive tumors; and it is not eliminating the 
estrogen receptor negative tumors, the ones that we 
typically think of as bad actors from a survival standpoint, 
which I think is what patients should be interested in, in 
the long run.  This might suggest a lesser long-term 
survival advantage. 
	DR. WOLMARK:  Well, I am not sure that we are not 
eliminating the larger tumors, or that we are not 
eliminating tumors with four or more positive nodes.  I 
mean, these are the characteristics of the tumors that we 
see that are evolving on tamoxifen. 
	As far as what the ultimate outcome is going to 
be, I think if you can eliminate breast cancer at some point 
in its evolution, I think we have no way of knowing whether 
that breast cancer would go on to become virulent and 
eventually kill the patient.  So, I don't think that we can 
really comment with any degree of accuracy on what the 
ultimate effects are going to be vis-a-vis perhaps a less 
than expected impact on survival.  I think the fact that we 
can reduce it by 45 percent will ultimately translate into a 
prolongation in overall survival. 
	I don't think that there is any evidence that we 
are selecting out a more virulent variety of breast cancer 
as a result of the use of tamoxifen, and I think that we 
have to emphasize the fact that there has been I think a 
very clearly defined reduction in the overall rate of 
invasive and non-invasive cancer.  Beyond that, I think we 
can't speculate.
	DR. DUTCHER:  Miss Cassel?
	MS. CASSEL:  I am here today as a patient 
representative since I am considered high risk and a target 
population should the drug be approved.  How long would you 
prescribe the tamoxifen for me, so to speak, and at what 
age?  If I have been high risk for the last ten years, at 
what age would you prescribe it?  At forty?  At fifty?  And 
for how long?
	DR. WOLMARK:  The duration of tamoxifen that was 
used in this trial was for a period of 5 years, and we think 
that is an appropriate interval to use.  Of course, the 
question that comes up is how do you know that 10 years 
wouldn't be better?  Well, the answer is we don't know since 
that clearly was not tested in this trial.
	But we do have some information from NSABP 
protocol B-14, where we did compare 5 years versus 10 years 
of tamoxifen in patients who had a personal history of 
breast cancer who were negative, and whose breast cancers 
were receptor positive.  There, it was demonstrated, to our 
surprise, that 10 years was not only not better than 5 years 
relative to the index cancer but was slightly worse.  But of 
greater significance, addressing your question, is that 
there was no additional incremental benefit to the 
contralateral breast for the additional 5 years of therapy.  
So, we believe that 5 years is the optimum time until data 
to the contrary appear.  So, I would suggest 5 years. 
	As far as when it should be started, I mean, from 
my perspective, I think it should be started as soon as it 
is known that the risk is such that it would make the 
patient eligible.  If one has a 35-year old woman who is of 
such risk that she would fit the eligibility criteria for 
the NSABP study, I think that would be the time to initiate 
5 years of tamoxifen.  I see no virtue in waiting an 
additional 5 years to let the risk increase to start at a 
certain arbitrary time in the future.
	MS. CASSEL:  I am also concerned, in talking to 
some of the target population, that women have a feeling 
that is a false safe feeling -- I have the drug, almost as a 
birth control pill, and I can just take it and not worry 
about it.  I am afraid that they will forget their 
self-breast exam, their mammogram.  This is the feeling of 
some of the women.
	DR. WOLMARK:  Well, I think we have to be very 
cognizant of that, and I think that we have to indicate very 
clearly that this is not a substitute and that we have to 
continue to exercise the standard of medical care and the 
standard of screening. 
	DR. DUTCHER:  Dr. Raghavan?
	DR. RAGHAVAN:  I have just a couple of questions.  
I always get a little nervous when two-thirds of the deaths 
on a list are listed as "other."  I recognize that the other 
deaths from placebo are more common than from tamoxifen, but 
would you give us a little more information about that broad 
category?
	DR. COSTANTINO:  I believe a complete list is 
included in the document that you were provided, but to give 
you some examples -- let's see, we talked about the 
breakdown of the cancers -- I am not sure how much detail 
you want me to go through.  We have about 20 different 
causes, but these are deaths due to brain cancer, 3 versus 
1; breast cancer 5 versus 3; colon, 1 and 1; endometrial 1; 
lung cancer 10 and 8; ovarian cancer 1 and 2; lymphatic 
system 4 and 1; pancreas 6 and 2.  Of course, the first is 
the placebo arm. 
	Moving down to heart disease, ischemic heart 
disease 12 and 12; stroke 3 and 4; pulmonary embolisms 0 and 
3; unknown causes 4 and 4.  Then there were 9 and 7 
miscellaneous causes, which accounted for 11 different 
categories which, from the top of my head, I don't really 
know.  But there was no indication that there was any type 
of cause of death which was predominant arm more than in the 
other.
	DR. RAGHAVAN:  And was there a systematic 
requirement for autopsies where possible?
	DR. COSTANTINO:  There was no requirement for 
autopsy.  We did obtain the death certificates and we did 
obtain information from autopsy if it was performed, but 
there was no requirement that autopsy be performed.  In 
other words, this is a community-based study.  So, we had to 
accept whatever standard of care is going on in the 
community. 
	DR. RAGHAVAN:  You commented that there was 
really, I guess, an anticipated absence of ocular problems 
and, in fact, maybe a reduced level compared to what was 
expected.  Did you have a mechanism where the participants 
were actually routinely examined by physicians looking for 
specific indices?
	DR. COSTANTINO:  There was no routine examination.  
Our follow-up consisted of at every visit there was a series 
of questions that the women were asked.  The first question 
was "have you had an eye exam since the last time you 
visited our clinic, and if you did, what were the findings 
from that eye exam?"  There was also a series of questions 
specifically aimed at determining vision changes, asking 
them specifically "have you noted changes in your vision? Do 
you have more difficulty driving at night?" or different 
types of things which were included in the questionnaire. 
So, we have all these screening types of things. 
	Also included as part of our follow-up was that 
the institutions were required to obtain discharge summaries 
documenting the diagnosis for all incidents for inpatient 
and outpatient visits.  So, from these types of things there 
is another mechanism for us to identify women who might have 
had eye surgeries or eye problems that required some type of 
inpatient or outpatient care.  But we did not have a routine 
eye exam. 
	DR. WOLMARK:  The data from protocol B-14, the 
that trial where some 303 patients were evaluated for eye 
changes, that too was a tamoxifen versus placebo controlled 
trial.  That was done in a definitive manner with 
ophthalmologic examinations, and there I think it was noted 
prospectively that the changes in the retina, or crystals, 
or edema, or macular degeneration was not in evidence. 
	DR. RAGHAVAN:  My final question, Norm, if you 
look at your Gail model, the results are really very 
impressive for the 5-plus group, and there clearly is a 
difference with low level of risk, and I am also struggling 
a little in terms of the hazard ratios in the less at risk 
group.  Can you talk about that a little bit?
	DR. WOLMARK:  Well, Jo showed a slide based on 
risk categories, and in each category there was a reduction.  
How does one translate that into clinical practice?  I think 
the report from the FDA to ODAC which summarizes our view, I 
think, very clearly is that it really boils down to an 
individual choice and an interpretation of risk and benefit, 
and not every individual will do that in the same way.  I 
think we have to provide the potential participant with a 
clear overview of the information, given in a very 
definitive manner, and then I think it becomes a matter of 
individual choice, particularly for those areas that you 
allude to, where the risk is below the 5 or the 6 that you 
allude to.
	DR. ALBAIN:  Just to follow that up, and then I 
have a new question.  At least in your briefing book the 
hazards do cross the confidence intervals around the 
hazards, cross 1, in some of these other subsets.  Your 
predefined strata for risk that you put into the 
randomization were a bit different than these that appear 
here.  Could you comment on what the hazards actually are 
for the confidence intervals?
	DR. COSTANTINO:  When we stratified at 
randomization we used relative risk.  Those are categories 
of relative risk.  Actually, the relative risk was defined 
as your 5-year risk relative to an individual of the same 
age and race but who did not have any risk factors.  The 
reason that we decided to use absolute risk as the 
categorization is because absolute risk is a much cleaner 
mechanism to do that.  Two people could have the exact same 
relative risk but have absolute risks which are totally 
different.  Therefore, when we did the analysis we wanted to 
control for that factor, and the easiest way to do that is 
to stratify by levels of absolute risk. 
	DR. ALBAIN:  Then I would like to turn to some 
other populations at risk, in particular DCIS and the 
African-American population.  Certainly, you were not 
choosing DCIS as a primary endpoint but your results are 
intriguing, and we are also aware you have another trial 
that has addressed that specifically prospectively.  Do you 
feel that the data are robust enough in P-1 to add DCIS to 
the labeling, or must we wait a bit longer, and how much 
longer for your other study?
	DR. WOLMARK:  I think we must wait, and I don't 
think we will be waiting too long.  DCIS was not an entry 
criterion for this trial.  So, I think we have to rely on 
the data from B-24 and B-17 prior to that, which I think 
will probably require a different session of this group. 
	DR. ALBAIN:  But you did show prevention of DCIS 
that was quite striking.
	DR. WOLMARK:  Yes, I think to prevent DCIS --
	DR. ALBAIN:  That is what I mean.
	DR. WOLMARK:  -- based on the entry criteria that 
we utilized in this trial, very much so.  I think it 
decreases the rates of non-invasive breast cancer, 
predominantly DCIS.  I completely agree with that.
	DR. ALBAIN:  And then the African-American 
population, you tried very, very hard prospectively to 
accrue minority communities.  Could you comment on that 
effort, and then how you feel these results could be 
translated to that population?
	DR. WOLMARK:  I would like to ask Dr. Wickerham to 
comment on that.
	DR. WICKERHAM:  Dr. Albain, you are right.  This 
is an effort that the NSABP has taken very seriously from 
the start of the trial, and during the study we spent 
considerable effort to try to increase accrual from these 
various populations.  Our goal at the outset of the trial 
was to have a population to reflect women at risk.  Despite 
these efforts, we were not fully successful at that.  Only 
about 3 percent of the women entered are women of color.  
That really doesn't allow us to make definitive statements 
relative to these results in those populations.  But you 
should be aware that in our that trials we were more 
successful in entering women from those groups, 10-12 
percent, 15 percent in some of our trials.  B-14, which in 
many ways forms the basis for the prevention trial, has been 
evaluated and analyzed relative to response to tamoxifen in 
these populations, and we clearly see no difference in the 
outcomes. 
	DR. DUTCHER:  Dr. Ozols?
	DR. OZOLS:  Getting back to the risk again, the 2 
major side effects, endometrial cancer and thromboembolic 
disease, and the 3 deaths in the that group with the 
pulmonary emboli, can you get any better profile on which 
women, you know, may be at risk for those 2 toxicities?  The 
traditional risk factors associated with endometrial cancer 
-- diabetes, hypertension, obesity, are those heightened by 
tamoxifen?  Likewise, can you identify anybody who may be at 
higher risk for developing pulmonary emboli?
	DR. WOLMARK:  Well, we obviously examined that, 
and we are not able to come up with a profile that would 
identify a subpopulation that would be at inordinate risk, 
such that they could be eliminated from entry into this 
trial.  We did, however, a priori eliminate those 
individuals who had a previous personal history of deep vein 
thrombosis or pulmonary emboli.  But examining the actual 
data of the population that was entered we could not define 
characteristics that would be associated with increased risk 
for those events. 
	DR. DUTCHER:  Just to follow up on that, about 25 
percent of people who were screened and met eligibility 
actually entered the trial, and a comment was made about 
medical reasons for exclusions.  Was it medical exclusion or 
was it logistic exclusion?  What was the drop-off between 
those that met the eligibility and those that actually 
entered the study?
	DR. WOLMARK:  Following the risk assessment, those 
who were eligible from the eligibility and those who were 
actually randomized. 
	DR. COSTANTINO:  I think the biggest reason for 
the drop was that women were not interested in participating 
in the trial.  They did not go forward to have the 
full-fledged medical evaluation.  A little over 14,000 women 
actually went to that level to be medically evaluated to 
come into the trial, and out of that 14,000-plus 13,388 were 
actually randomized.  So, the major reason for the drop from 
57,000 down to the 13,000 was because women were just not 
interested in being a participant in the trial. 
	DR. MARGOLIN:  I have what I think will turn out 
to be 3 questions.  The first one is sort of a biology 
question and it pertains to the question that Miss Cassel 
asked earlier on about the best timing for intervention in 
patients who are identified as subjects at risk.  It is just 
hard to imagine that 5 years of that at basically any time 
in a woman's life is going to infer a permanent change in 
her likelihood of developing invasive or non-invasive breast 
cancer. 
	I am wondering, based on preclinical models or 
based on any biology that anybody knows, whether, say, early 
treatment and then some period of time off therapy and then 
reintroduction of therapy, or if we can somehow improve on 
what we are trying to do here to prevent breast cancer.
	DR. WOLMARK:  I think we are really limited by the 
data that we have, unfortunately.  I mean, we would like to 
know where tamoxifen acts in this situation.  We would like 
to know what the molecular mechanisms are.  Yet, this was a 
clinically driven trial and we are left with clinical data.
	Is there an optimum time at which the intervention 
should be undertaken that would be better than just starting 
it when the relative risk becomes apparent?  If one were to 
undertake such a trial clinically, it would require enormous 
numbers of participants with an enormous amount of support 
from the agencies, to whom we are forever grateful -- the 
NCI and Dr. Ford -- and I don't think at this time it is a 
practical endeavor.  I mean, we would much rather go on and 
determine if we can find drugs that perhaps have the same 
efficacy with fewer side effects which would make that issue 
moot to a certain extent because they could be given longer 
and with greater degree of definitive intervention.
	DR. MARGOLIN:  Thank you.  My second question is I 
believe the study was noted as being insufficiently powered, 
or at least was closed at a point where it was 
insufficiently powered to detect survival differences.  Is 
it expected that after a certain number of events have 
occurred, after a certain follow-up, that we will be able to 
see a potential survival difference, or is that just not 
going to be possible with this database?
	DR. WOLMARK:  If we were to have primarily done a 
survival endpoint, I think we would have required an 
additional 10 years of follow-up and a considerably greater 
sample size, but I would like Dr. Costantino to comment on 
what it would have taken to have configured this trial for a 
survival endpoint for breast cancer.
	DR. COSTANTINO:  We never did design the trial to 
be able to have the power to detect a survival difference 
because it would have required doubling the sample size and 
much longer follow-up, as Dr. Wolmark indicated.  We do plan 
to continue following those women.  We will learn more 
information about survival benefits, but it is highly 
unlikely that we will ever have statistical power to show a 
significant difference in survival.  It requires larger 
numbers and a longer follow-up period.
	DR. MARGOLIN:  I have one additional question, 
whether there are plans to go back and do some genetic 
studies of subjects enrolled in order to detect potential 
interactions with BRCA 1 and 2 or other genetic risk 
factors. 
	DR. WOLMARK:  Yes, that is I think an important 
commitment and those trials are about to be launched.  
Certainly, that is a very important issue.  We have 
collected serum and lymphocytes from the women who 
participated in this trial, and we will start to analyze 
BRCA 1 and 2.  Mary Clare King will be doing this in the 
very near future.  We will be able to determine definitively 
what the benefit is in those individuals who have BRCA 1 and 
2 abnormalities.  Additional comments?
	DR. SCHILSKY:  A quick comment and a question.  It 
is striking to me that the leading cause of cancer death in 
this study is lung cancer.  It is too bad tamoxifen doesn't 
prevent that. 
	DR. WOLMARK:  Oh, there wasn't a reduction in 
that?
	[Laughter]
	DR. SIMON:  The question I guess has to do with 
how the participants in the study have now been informed of 
the results, whether women who were randomized to placebo 
have been advised to take tamoxifen and, if so, how might 
that confound the future interpretation of the results with 
continuing follow-up?
	DR. WOLMARK:  We have a covenant with the 
participants that they would be among the first to know the 
data, and we did not want to repeat the unfortunate events 
of some of the earlier episodes that affected this trial 
where the participants learned what was going on from the 
newspaper.  Despite our diligent efforts to avoid that, we 
were not entirely successful in this trial since the data 
were previewed in a well-known newspaper prior to the time 
that we were able to transmit that information through a 
widely publicized press conference that I believe took place 
on April 4. 
	The participants have been formally apprised.  
That process was in place as the data were being 
disseminated, and those individuals who were on placebo are 
given the opportunity to go on 5 years of tamoxifen.  Zeneca 
has been very gracious in providing that medication to these 
participants.  Also, those individuals who did not complete 
the 5 years of tamoxifen who were randomized on this trial 
will have the opportunity to complete the full 5 years of 
tamoxifen.
	As far as what does that do to our ability to 
continue to monitor the differences between tamoxifen and 
placebo, clearly those are attenuated in that this trial has 
been unblinded and that we will now have crossovers, but to 
what extent we do not know as yet.  We will obviously 
continue to follow these patient cohorts and, certainly, 
those that are on tamoxifen will continue to provide data, 
and we believe we can continue to model the events in the 
placebo arm.  So, I think it will provide useful information 
but the primary endpoint of the trial is obviously affected 
by the unblinding.
	DR. DUTCHER:  Dr. Simon?
	DR. SIMON:  I have several questions.  One, 
several people have noted the concern about the limited 
follow-up.  There is not a whole lot that can be done about 
that, but you have basically presented data that was 
available to the data monitoring committee last January.  
Can you give us updated data on number of events in the 
placebo and tamoxifen group for the 3 age groups for 
invasive breast cancer?
	DR. WOLMARK:  Obviously, you know, the data 
provided to this committee are the data that are going to be 
utilized so I would rather not go into the data for the 
updated analysis, only to tell you that the differences are 
even more compelling.
	DR. SIMON:  Why do you not want to give us the 
updated data?
	DR. WOLMARK:  I think that we had a cut-off that 
we all agreed to a priori; that this was submitted to this 
committee for their review; and I think that is the data set 
that is going to have to be used to make the decision.
	DR. SIMON:  Well, typically, you know, when you 
present data to a data monitoring committee that is not up 
to date to that minute anyway.  You know, there is a 
distribution of time since patients were last seen and 
evaluated.  So, that data actually may be a year old at this 
point really in terms of what it represents in terms of when 
patients were last seen.
	Well, let me go on to my next question.  Do you 
have information about the hazard rate over time for the 
ER-negative cases, particularly in the tamoxifen arm?
	DR. WOLMARK:  Jo, the hazard rate for the 
ER-negative cases in the tamoxifen arm?
	DR. COSTANTINO:  Over time?
	DR. WOLMARK:  Over time. 
	DR. COSTANTINO:  I don't have that with me.
	DR. WOLMARK:  The answer was no, he does not have 
it with him, and he wondered why you were asking the 
question.
	DR. SIMON:  Well, because really, you know, one 
question is whether you are treating with tamoxifen in 
subclinical cases that might have materialized as 
ER-positive tumors -- by the selection process will 
materialize as ER-negative tumors, and whether you will see 
that there is some trend of that happening in later periods 
of follow-up.
	DR. WOLMARK:  Jo?
	DR. COSTANTINO:  I can tell you that we didn't see 
that kind of trend.  If you consider that the ER-positive 
tumors were 80 percent of the tumors and we did see hazard 
rates over time that were constant, we would suspect that 
just taking out those majority of things is not going to 
change the pattern, but I didn't see the type of pattern 
that you were suggesting. 
	DR. SIMON:  I have a couple of other questions.  
One is that I have some concern about what we are supposed 
to conclude in terms of what group of patients these results 
apply to.  One, it is one thing to say what the eligibility 
criteria were and that is not to say what patients actually 
entered the trial.  In terms of communicating these kind of 
results in terms of who these results apply to, it is really 
not an issue of even simplifying in a user-friendly way the 
Gail model.  The real issue is what women went into this 
trial, because there may be women who were eligible 
according to the Gail model but if they are not well 
represented in this trial then we probably can't have much 
confidence that the results apply to them.  I guess I 
haven't really seen a clear explanation of what the women 
looked like who went into this trial.
	I guess the second issue is that it is one thing 
to say that the risk of breast cancer of a woman is 
equivalent to that of a 60-year old woman, and it is 
something else to say that the results actually apply to a 
60-year old woman.  Most of these women, I think two-thirds 
of them or something like that, were under the age of 60 and 
they got into this trial because they had other risk 
factors.  So I think we have to be somewhat careful in 
assuming that because the Gail model said that their risk 
factor was at least the risk of a 60-year old woman that the 
results actually apply to a 60-year old woman.  The only 
basis we have for that is, you know, where you break it down 
by age.  You know, that is a relatively small subset.  It 
looks like the effect is just as great for them as it was 
for the other women.  But I think we really have to be very 
careful in trying to sort out who the results apply to.  
That is sort of a comment, not a question.
	I do have one other question, and I would like to 
sort of get your general medical interpretation of it.  
There were 69 fewer cases of invasive breast cancer on the 
tamoxifen arm, but there were 19 additional cases of 
endometrial cancer.  There were 39 more cases of vascular 
events on the tamoxifen arm, and there were 38 more cases of 
cataracts requiring surgery.  So, how do you make that 
risk-benefit equation? 
	DR. WOLMARK:  Well, I don't think it should be up 
to me nor any other physician or someone who delivers health 
care to compel anyone to go on tamoxifen or not go on 
tamoxifen.  I think that it becomes an individual decision 
after the risk and benefits are thoroughly reviewed and 
after that information is transmitted in a very clear and 
well-defined manner.
	Having said that, and since you asked for an 
opinion, I think that there are categories that, from my 
perspective, clearly fall out where the benefits 
unequivocally outweigh the risks.  I think those subsets 
would include those women who are under 50 years of age 
where the excess of adverse events is small; those women who 
are over 50 years of age who have had hysterectomies, and in 
our patient population that accounted for a substantial 
proportion; those women who have had a personal history of 
lobular carcinoma in situ; and those women who fulfill the 
eligibility criteria and also have atypical hyperplasia.  I 
think in those instances, from my perspective, the benefits 
clearly outweigh the risks. 
	I think in the other categories it boils down to 
an issue of personal choice and personal decision.  I think 
what some people would consider as inordinate risks others 
would gladly accept. 
	DR. DUTCHER:  Miss Beaman?
	MS. BEAMAN:  Would you reference the data that you 
have for the women who were taking tamoxifen and developed 
breast cancer as to whether this cancer was of the more 
aggressive type?
	DR. WOLMARK:  I think in the slides that were 
presented relative to the distribution of women who did 
develop breast cancer while they were on tamoxifen there 
certainly was no evidence, from a nodal standpoint as well 
as a tumor size standpoint, that the tumors that developed 
on tamoxifen were more aggressive or more virulent than 
those tumors that developed in women who were taking 
placebo.  So, there is no evidence that tamoxifen culls out 
a more virulent subset of breast cancer while suppressing 
the more benign forms of breast cancer.  I think that 
appears in the slides that you have in the handout. 
	DR. DUTCHER:  Dr. Johnson?
	DR. JOHNSON:  Actually, I want to follow-up, if I 
may, on what I think Dr. Sledge addressed earlier.  
Certainly, nodal status is one of the most important, if not 
the most important, prognostic factors and size as well but 
there is no mention about tumor grade here which clearly has 
an impact.  If all 154 tumors that appeared on placebo were 
low grade and all 85 on tamoxifen were high grade tumors 
there might, in fact, be a difference in outcome even though 
the other factors were identical.  I wonder if maybe you 
have some data regarding grade.  I didn't see any of that 
information.
	DR. WOLMARK:  No, we have no data on grade.  I 
think it would be nice to know what the HER2 status of the 
tumors was, and is, and will be, but we don't have that 
information.
	DR. JOHNSON:  Is that information that we can 
expect will be forthcoming in the future, or is it simply 
something that won't be followed-up upon? 
	DR. WOLMARK:  We are collecting slides and blocks, 
which the protocol has mandated, on all events that occur in 
this study and, hopefully, that information will eventually 
be forthcoming. 
	DR. JOHNSON:  And, if I may follow-up with one 
further question, the death rate from breast cancer, as has 
been pointed out, is really rather small in the trial 
overall and it is similar in the 2 arms which, actually, is 
sort of interesting given the fact that the number of 
overall cancers is twice as great on the placebo arm.  So, 
do we have any information about the status of those women 
who have developed breast cancer at this juncture?  Again, 
just to take the extreme, if all 85 of the women on the 
tamoxifen arm now have stage 4 disease and all 185 on the 
placebo arm have stage 1 disease there may be an indication 
of a difference in the aggressiveness of the tumors.  Do we 
have that data?
	DR. COSTANTINO:  We are collecting information 
regarding recurrence, and we do have that but it is not 
complete at this stage.   Dr. Paik is in the process of 
reviewing all the pathology slides as we speak but we do not 
have that information accumulated as of yet. 
	DR. WOLMARK:  But, David, why would you think that 
there would be that disparity?
	DR. JOHNSON:  Well, because unlike George, I don't 
have the ability to see the future. 
	[Laughter]
	He predicted that this drug was going to work and 
I just didn't realize it was going to work.  So, I was 
really happy that the study was done.  So, you know, data is 
what really drives my decision-making, or I like to think it 
does.  So, I don't believe that is the case.  Just because I 
asked the question doesn't necessarily mean I believe that 
is the answer.  I think I would like to know, and I am sure 
everyone sitting over here as well as in the audience would 
like to know those data as well.  And, if it were to turn 
out that way, then it would be disturbing. 
	DR. WOLMARK:  George, perhaps you could save us a 
lot of time by telling us raloxifene versus tamoxifen for 
the STAR trial?
	[Laughter]
	DR. SLEDGE:  I would be glad to tell you that 
afterwards. 
	DR. DUTCHER:  Dr. Margolin?
	DR. MARGOLIN:  I have one question and one 
comment.  The question is that -- unless I have missed it 
and it has already been presented -- we have heard at 
various times well before this meeting that the subjects who 
were accrued or registered to this trial turned out to have 
higher at least relative risk of breast cancer than was 
expected and was planned for the original accrual.  I am 
curious to know, at the end of the trial, at least based on 
the placebo arm data, whether the incidence of breast cancer 
reflected what was expected based on that revised accrual 
estimate. 
	DR. COSTANTINO:  Indeed, it did.  It was about 
double what we expected.
	DR. MARGOLIN:  Thank you.  My comment is that if 
the drug is approved for this indication, and I think that 
the world, certainly the U.S. but the world really worships 
what the NSABP says and does, and the NCI as well, and it 
would be very crucial that very firm guidelines be given in 
terms of selecting subjects for that with this type of 
intervention.
	DR. ALBAIN:  I have a question for the sponsor.  
Your choice of wording in the indication, using the word 
"prevention."  Typically, when that word is used you have 
the luxury of long-term follow-up, in particular like we do 
in B-14 and the worldwide overview for prevention of 
contralateral breast cancers.  Would you consider perhaps 
softening that statement to say reduction in risk of 
occurrence of first cancers because that is really what we 
have seen quite dramatically by this data?
	DR. SIMON:  Right.  Actually, that is what was 
seen in the overview also in the contralateral breast, and 
we would agree with you.  I think "prevention" means it 
doesn't occur and it also means risk reduction.  What we are 
looking for here is a way of getting the message across to 
the average person.  It means something to us.  The trial 
was called prevention; Dr. Leslie Ford's group is 
prevention.  We are not preventing all breast cancers.  
Clearly we are not.  But this is a major step forward, and I 
would like to think that we could retain the term 
"prevention," describing it as it was described in the 
manuscript which states that it is a reduction in the number 
of breast cancers that are anticipated. 
	DR. DUTCHER:  Dr. Simon?
	DR. SIMON:  The women over the age of 60, were 
they a representative group of women or did they have high 
risk features?
	DR. COSTANTINO:  Actually, if you look at the 
hazard rate in the placebo, you can see that their risk of 
breast cancer was among the highest of all the women in the 
trial.  So, it is true that being over 60 was an eligibility 
criterion and so you got in, so your risk could be as low as 
1.66 theoretically but, indeed, the rate and the hazard in 
the placebo group was over 7/1000.  So, they were 
essentially comparable in risk to the women in the other 
groups.  As far as being representative, I think you mean 
representative of the general population?
	DR. SIMON:  Right.
	DR. COSTANTINO:  I don't think any of these women 
are representative of the general population because they 
have been selected out to be at high risk for breast cancer.
	DR. SIMON:  So, how do we know --
	DR. COSTANTINO:  They volunteered for the trial.
	DR. SIMON:  So, how do we know that these results 
apply to a typical spectrum of women over the age of 60 in 
the United States?  How do we know who these results apply 
to? 
	DR. COSTANTINO:  We know the results are 
consistent across all categories or risk --
	DR. SIMON:  No, but you say age and you show over 
60, but these are not a representative group of women over 
60.
	DR. COSTANTINO:  That is true of any clinical 
trial.  I think the best we can say is that within the trial 
we were not able to demonstrate any population which did not 
show benefit from the treatment; that we can think of no 
reason to conclude that the women in the trial, as far as 
effect is concerned, would not represent the general 
population.  So, I don't see that we can do more than that.
	DR. SIMON:  So, what is your proposal for who you 
are recommending this for in terms of an indication?  Is it 
women whose risk would satisfy the Gail model?  And, if that 
is the case, that would include all women over the age of 60 
but we don't really have any indication that these results 
apply to typical women over the age of 60.  So, I find that 
a real inadequate specification of who these results apply 
to.  Can you clarify it for me?
	DR. COSTANTINO:  I just don't understand your 
argument, Richard. 
	DR. SIMON:  Well, maybe I can clarify it.  You 
have a study of high risk women and this study seems to have 
shown a benefit of tamoxifen for this group of women, and 
now we are trying to figure out who this group of women are 
before we wind up recommending this drug, with its side 
effects, for all women.  If we recommend it for all women 
whose risk is at least equivalent to that of 60-year old 
women, then we recommend it to a large group of women over 
the age of 60 in this country who probably may not have been 
represented at all in this clinical trial.  You may have 
gotten a result that worked because of some genetic features 
that these women had that gave them other high risk features 
that really don't have anything to do with your typical --
	DR. COSTANTINO:  The eligibility criteria for this 
trial was simply being over 60.  It had nothing to do with 
the Gail model.  We are recommending that those same type of 
criteria be applied to women who are considered candidates 
for the drug.  Simply being over 60 makes you a candidate so 
that you can go forth and make these kind of comparisons of 
the risks and benefits and decide.  For women who are under 
60, we are recommending using the Gail model just as it was 
applied as eligibility criteria.  So, our recommendations 
are pertaining specifically to the exact same type of women 
who were deemed eligible for the trial.
	DR. SIMON:  Well, that is what I was saying.  
There is a difference between being eligible and who 
actually got into the trial.  I think when you make 
recommendations as to who the results of the trial apply to, 
you have to look at who was in the trial, not who was 
eligible for the trial. 
	DR. WOLMARK:  Richard, I really agree with Jo on 
this.  I think that this is an inherent problem in every 
clinical trial you do.  You set out the eligibility criteria 
and whoever actually enters the trial may or may not, you 
know, fulfill the entire spectrum of the eligibility 
criteria but that does not justify anyone from going back 
and retrospectively culling out a subset to say that this is 
more representative of those individuals who actually 
entered the trial.  We don't have the power to do that, from 
my perspective and, more importantly, I don't think we have 
the right to do that.
	DR. SIMON:  I am just trying to figure out whether 
the results of this trial apply to the typical woman over 
the age of 60 who doesn't have other high risk features.
	DR. DUTCHER:  Dr. Honig?
	DR. HONIG:  We were concerned about that also with 
that particular age group, and I don't have the numbers with 
me but we looked at women over 60 to see if, for example, 
all of them had positive family histories, or a significant 
proportion had LCIS or atypical hyperplasia, and that was 
not true.  At the time though we did not have the risk disc 
so we couldn't run the Gail models, but most of them appear 
to have a combination of the other factors that went into 
the Gail model, if that helps answer your question in part.
	DR. WOLMARK:  Yes, I think we apply, you know, 
what we believe and we will be using the criteria for the 
next NSABP trial, the study of tamoxifen and raloxifene as 
they were used for the BCPT, with the exception that this 
will be limited to postmenopausal women. 
	I think it would be a mistake and somewhat 
disconcerting to try and fine-tune the characteristics of 
patients who would benefit from tamoxifen based on a subset 
analysis of the NSABP population.  I think we should use the 
criteria as they were applied to the BCPT.
	DR. LEWIS:  I would just like to comment that 
there was one other criterion that was left out, and that 
was a discussion with the patient, and we plan, working with 
the National Cancer Institute, to stress this as a critical 
part of a decision for a woman which empowers the woman to 
elect to take tamoxifen.  Certainly it is not Zeneca's 
intention to take all women at 1.66 and say that tamoxifen 
is right for them.  As a matter of fact, in our label there 
is a sentence which says tamoxifen is not right for all 
women at high risk -- something to that effect, and we do 
plan to handle that responsibly. 
	DR. DUTCHER:  Dr. Sledge?
	DR. SLEDGE:  I would like to get back to Dr. 
Albain's comments a few minutes ago.  On this question of 
prevention, I think it is reasonable to ask whether what we 
are seeing in this trial is true prevention.  If we look at 
the risk ratio by year, a great point was made that it was 
pretty consistent over the first 5 years.  It is real hard 
for me to believe that what I have always thought of as 
chemoprevention, that is to say, the transition from an 
earlier to a later place along the stage of development of 
cancer is what you are seeing when you don't see a cancer in 
the first year of a trial, and I think we have to assume 
that what we are dealing with in the early years is 
chemosuppression of existing invasive tumors rather than 
true chemoprevention. 
	DR. WOLMARK:  I would have no argument with that.  
And what are we seeing in later years? 
	DR. SLEDGE:  Well, presumably the later out you 
get, the more likely you are to be seeing chemoprevention.  
I don't think there is any argument about that, but I think 
to say that all of these early cases where we are seeing a 
difference represent chemoprevention just simply probably 
isn't true. 
	DR. WOLMARK:  Yet, the ultimate effort is to 
reduce the incidence of invasive cancer, reduce the 
incidence of non-invasive cancer and its clinical 
consequences.
	DR. SLEDGE:  I think we can agree on that.
	DR. DUTCHER:  Dr. Margolin?
	DR. MARGOLIN:  I would like to know whether the 
data on the effect of tamoxifen in this cohort reduced the 
expected risk of breast cancer down to that of an 
age-adjusted woman with no additional risk factors, or if it 
is still higher by some relative risk.
	DR. WOLMARK:  Jo, do you want to comment? 
	DR. COSTANTINO:  Let me make sure I understand 
your question.  Your question is --
	DR. MARGOLIN:  Does tamoxifen normalize the risk 
of breast cancer?
	DR. COSTANTINO:  Did it bring it back to 
essentially no excess risk?  I have not specifically done 
that analysis to compare the women on the tamoxifen arm to 
what would be expected, but without having done that I can 
say I am sure it did not take it all the way down because in 
general the rate on the tamoxifen arm was about 3.4/1000 
consistently across all ages, and I know that is not the 
baseline rate for women who don't have any risks.
	DR. MARGOLIN:  So, that information would be a 
necessary part of the counseling in terms of the subjects on 
this treatment.
	DR. WOLMARK:  It reduces it 45 percent overall in 
this analysis, but not back to baseline. 
	DR. DUTCHER:  Dr. Albain?
	DR. ALBAIN:  It is not preventing ER-negative 
cancers essentially, among a few others probably. 
	DR. WOLMARK:  I think one can theorize that is the 
case. 
	DR. DUTCHER:  What is the long-term follow-up plan 
on this study?
	DR. WOLMARK:  We will continue to follow these 
patients as long as we and they continue to agree to be 
followed. 
	DR. JUSTICE:  I would just like to follow-up on 
that question.  I think there was perhaps some 
mis-communication about the updated data.  I think I agree 
with what Dr. Wolmark says, that we don't want the updated 
data presented today.  We will certainly ask to see it, and 
we will certainly ask to see follow-up data on both efficacy 
and safety, but we haven't actually seen the updated data 
and we don't want a lot of different numbers floating 
around.  So, I think that is the hesitation Dr. Wolmark had, 
not that he is not willing to provide us with it. 
	DR. WOLMARK:  I think that was very elegantly 
stated. 
	DR. DUTCHER:  Are there any other questions for 
the sponsor?  If not, we are going to take a 15-minute 
break.  We will be back here at 10:20.
	[Brief recess]
	DR. DUTCHER:  We are going to begin the FDA 
presentation. 
FDA Presentation
	DR. HONIG:  Thank you.  I will be presenting the 
FDA analysis of tamoxifen for prevention of breast cancer in 
women at high risk. 
	[Slide]
	In every FDA presentation you see a slide similar 
to this one, but I would like to emphasize that for this 
review in particular it was truly a collaborative effort to 
be able to review this much material, on this many patients 
in such a short time frame. 
	I wish I had time to detail everyone's 
contributions but I would particularly like to mention 
several people.  Donna Griebel, another medical reviewer in 
our Division who reviewed and analyzed the case report forms 
for stroke; Karen Johnson who, prior to her departure from 
FDA, reviewed all of the case report forms for invasive and 
non-invasive breast cancer; and Alison Martin, who analyzed 
and reviewed all the case report forms on the endometrial 
cancer patients in this study. 
	I would also like to spend a minute talking about 
the administrative time line because it was certainly a 
challenge for everyone involved in the application to be 
able to process and submit this much data, and also to 
review it in a timely fashion.
	[Slide]
	As you have heard, on April 2 the NCI and FDA were 
notified that there were significant efficacy results in 
this trial.  On April 23, there was a pre-sNDA meeting 
designed to facilitate the submission of the application in 
a timely fashion.
	Along those lines, FDA agreed to accept the report 
that had been prepared for the ERSMAC committee and the BCPT 
technical report in lieu of a study report, and also asked 
that the draft manuscript of P-1 be submitted as soon as 
possible to us.  Of course, the NSABP was busy with a number 
of other commitments, as well as trying to write that 
manuscript which was submitted.  We waived the requirements 
for the integrated summaries of safety and efficacy, and it 
was agreed that the data would be submitted electronically.  
On April 30, 1998 the SNDA was submitted and, as you can 
see, we are here 4 months later at ODAC to discuss the 
results.  
	[Slide]
	When we initially received the electronic database 
tables, it was clear that there were some limitations.  We 
didn't have primary data which is usually the type of data 
that we review.  For example, the primary endpoints were at 
first listed yes/no without dates, and we didn't have any of 
the characteristics of the breast or endometrial cancers 
that occurred on study, and we didn't have a complete list 
of risk factors.  But we had multiple discussions with 
NSABP.  We ironed out some of the technical problems in 
transferring the data and, as you can see, we, in fact, 
worked out a way for these to be submitted. 
	[Slide]
	We got the first additional set of requested 
elements on July 23, and the last set of data was submitted 
to us on August 4 so that we were able to go through the 
majority of this data in time for ODAC. 
	[Slide]
	As is usual in a clinical trial, we requested 
specific case report forms on participants in the trial.  We 
requested those for participants who had died during the 
study, who had developed both invasive and non-invasive 
breast cancer, endometrial cancer, DVT, PE and stroke.  With 
those listings we received approximately 625 that were 
submitted and reviewed in detail by the members of our team.
	[Slide]
	What I would like to do during this presentation 
is cover the following topics.  I don't want to go over 
details that have already been presented by the applicant, 
and I would like, instead, to concentrate on areas that 
perhaps we have a slightly different interpretation of or 
some additional information.
	[Slide]
	As you have already heard, NSABP P-1 is a large 
randomized, double-blind, placebo-controlled trial of 
tamoxifen for 5 years.  Again, you have already heard about 
the number of participants on study.  Most or the data are 
with reference to this denominator, however, 13,118 had 
additional follow-up and this is the denominator for certain 
of the adverse events, such as hot flashes, that we will be 
discussing later. 
	[Slide]
	I want to spend just a few minutes on the 
requirements for trial entry because this has a bearing on 
how this drug will be used in clinical practice if it is 
approved. 
	In the trial a multistep procedure was required 
for entry.  In the recruitment phase women were first seen 
and given information about the trial and had the 
opportunity to ask some questions about the study.  Then if 
they chose, they could fill out a risk assessment form that 
listed the risk factors for breast cancer that would be 
entered into the Gail model. 
	This risk assessment form was then forwarded to 
NSABP, and in a separate second protocol eligibility 
assessment the participant returned, having read materials 
at home, was able to ask and have more questions answered, 
and was able to discuss the actual risk assessment form 
generated by NSABP.  If at that point she wished to continue 
with study entry and she was eligible on the basis of breast 
cancer risk factors, she signed an informed consent and then 
proceeded with the staging studies required for entry. 
	It is worth noting that all eligibility factors 
were reviewed by the NSABP as well as by the local 
institution, and that includes both breast cancer risks and 
medical conditions.
	[Slide]
	In a third, separate visit at the study enrollment 
phase, the results of the studies  were reviewed.  If the 
participant were still willing to go on study and eligible, 
her informed consent was reaffirmed, and she was then 
randomized with a number of prospectively specified 
stratification factors. 
	So, this was a multistep process.  There were at 
least 2 institutions involved in ensuring that the 
participant was informed and eligible, the NSABP and the 
local site.  I mention this only because it is unlikely in a 
busy clinical practice that practitioners are going to be 
able to devote 3 separate visits to this level of detail.  
So, it is very important that we all develop patient 
education materials that will allow women to make an 
informed choice about whether they wish to take tamoxifen or 
not. 
	[Slide]
	There were many protocol amendments during the 
course of the study, however, I would say that there were 
probably 2 major protocol amendments and you have heard 
about some of these already.  One was that on September 24, 
1994 a requirement for baseline and annual endometrial 
screening for newly randomized participants was added.  
Participants who were already on the trial were offered 
screening but they could decline and continue on study.
	Also, in October of 1996 there was a formal 
decrease in the sample size based on the higher than 
expected number of events.  This had been prospectively 
specified in the protocol though.  It had called for an  
interim analysis to calculate sample size. 
	[Slide]
	In terms of on study conduct, the protocol said 
that you could be unblinded and know your treatment 
assignment if you developed invasive breast cancer, or if 
your physician felt that there were medical conditions that 
warranted knowing the treatment arm. 
	As you might expect, there were some non-protocol 
specified unblindings.  However, whether these occurred 
because the participants wished to know or the physicians 
wished to know based on a variety of medical conditions, 
these were all balanced between the 2 arms.  The "other" 
category is not other medical conditions but, rather, a 
separate category and you can see overall that there was 
really no difference.  We have examined all of these reasons 
in detail.  They were supplied by NSABP.  And, there was no 
difference. 
	[Slide]
	In terms of non-allowed medications on study, this 
is the information that the NSABP had in its database.  
Hormonal medications, which was an accumulated group of 
estrogen, progesterones, androgens, as well as a full 
complement of hormone replacement therapy.  They also 
collected information on oral contraceptive use; the use of 
open-label tamoxifen and raloxifene.  No one on study used 
raloxifene. 
	I really wanted to spend the time on the top line.  
As you can see, if you look at the women on placebo and the 
women on tamoxifen who are listed as using hormonal therapy 
at any time during the study, the number looks large.  But 
if you really restrict it and look at the number of women 
who used it while they were taking the study drug, it is a 
relatively small number.  Less than 1 percent actually used 
these medications.  This is in distinction to the European 
studies, which we will talk about later, which allowed the 
use of hormone therapy in various forms. 
	There were a few limitations of the database that 
I will review.  We did find some instances in the case 
report forms where women used hormonal therapy that were not 
in the database.  These were relatively few instances.  
Also, the database was designed to capture the date of the 
first use of these medications.  So, we don't have duration 
of use and we don't have multiple events of use. 
	Overall, our impression from looking at the case 
report forms is that it was still a relatively small number 
of women who used these medications for short times.  I 
think a good example would be women who had episodes of 
dysfunctional uterine bleeding who took short courses of 
Provera several times, for example. 
	[Slide]
	Compliance, as you have already heard was very 
high.  For women who started their therapy and subsequently 
discontinued therapy, the most common reasons are listed 
here -- hot flashes, anxiety, vaginal discharge.  The hot 
flashes and vaginal discharge are consistent with what is 
already known about tamoxifen and its side effects. 
	[Slide]
	I am going to move on to the endpoints of the 
study.  First, it is important to note that all events in 
all participants were reported unless the participant 
withdrew consent or was lost to follow-up.  In oncology 
treatment trials I think we frequently think about events 
being reported on drug or within 30 days of stopping drug.  
This is not the case here.  Overall, participants who were 
followed had all of their events recorded in the database. 
	In our review of case report forms we could find 
potentially 1 breast cancer that was perhaps not captured in 
the database.  We are still discussing this with NSABP.  The 
NSABP also set the rules up prospectively that the worst 
event per participant would be recorded.  So, if you had 
angina and then subsequently had an MI, the MI would be 
recorded but not each individual related event.  Similarly, 
if someone had a TIA and a CVA, it would be the stroke that 
would be reported in the database. 
	This was true for nearly everything except 
fractures.  That was in distinction where all of the 
fractures per participant were reported, not just the first 
fracture.
	[Slide]
	So, with regard to invasive breast cancer, you 
have already heard that there were 154 cases on placebo and 
85 on tamoxifen.  We looked at the number of cases that were 
diagnosed on each arm after stopping the study drug, and you 
can see that there are relatively comparable numbers on each 
arm.  Within the follow-up available to us on the study, 
there was no evidence of a rebound increase in the number of 
cases after the study drug, tamoxifen, was stopped. 
	We also saw reductions in the number of breast 
cancer cases in all the prospectively defined subgroups, 
specified by the sponsor.  In fact, we found reductions in 
every retrospectively defined subgroup that we could think 
of at FDA. 
	The reductions were seen in participants who had a 
family history, regardless of the number of affected first 
degree relatives.  We were able to carry this out for none 
and then 1 through 4, I believe.  We also saw reductions in 
participants who did not have a family history.  At first we 
were concerned that perhaps all the risk and all the benefit 
was being seen in a subgroup of women who were at risk 
because of a family history, and that was not true on our 
review of the database. 
	[Slide]
	The only subset in which this beneficial effect of 
tamoxifen was not observed was in women of color.  There 
were 486 non-white women entered on the study despite the 
really aggressive attempts on the part of the NSABP to 
recruit more women of color, and there were 9 cases, 3 on 
placebo and 6 on tamoxifen. 
	We looked at these women in detail.  The risk 
profile of these women didn't difference from that seen in 
the general population of women entered on the trial.  The 
characteristics of the 2 groups were not any different 
either.  They were not more aggressive or less aggressive. 
	At this point, I suppose you could say that it is 
unknown whether there is a differential effect in non-white 
women but we would favor the interpretation that overall 
women of color made up a small subset of the population and 
had relatively few events, and that we just don't have the 
statistical power to make any comments about that. 
	[Slide]
	In terms of the case report form review of the 
invasive cases, we agree that all the cases that were 
reported were, in fact, invasive breast cancer.  We assessed 
2 additional cases of invasive cancer on the placebo arm.  
These had previously been categorized as non-invasive breast 
cancer, and 1 on the tamoxifen arm as invasive cancer.  This 
was a woman who, after several reviews by NSABP, was 
ultimately assigned to the category of cancer of unknown 
primary and after our review we felt it was likely that she 
had breast cancer. 
	We also reviewed the assessed tumor size based on 
the original pathology reports.  We disagreed with the 
assessed tumor size for 3 cases on placebo and 1 on 
tamoxifen.  It resulted in minimal stage shifts for these 
participants and, as I mentioned before, we may have found 
an additional case that we are still discussing with NSABP.
	Overall though, even with these shifts in cases, 
it doesn't change the primary conclusion of the sponsor, 
which is that tamoxifen did result in a significantly 
decreased number of breast cancer cases on the tamoxifen arm 
compared to placebo.
	[Slide]
	This shows you the tumor size and nodal status 
distributions.  You have already seen this so I don't want 
to spend a lot of time on it except, again, to reiterate Dr. 
Costantino's point which was that tamoxifen was most 
effective in tumors that were less than 2 cm in size and in 
cancers that were either node negative or had 1-3 positive 
nodes. 
	[Slide]
	This shows the stage groupings for all of the 
cancers that were identified on study.  As is consistent in 
the general population, most of the women diagnosed with 
breast cancer had node-negative disease.  Some women had 
node positive.  There were 10 cases of inflammatory breast 
cancer, and 2 women who had either probably or confirmed 
metastatic disease at diagnosis but, again, you can see that 
they were not significantly different between the treatment 
arms. 
	[Slide]
	Again, you have already seen this slide showing 
that tamoxifen appears to have the greatest effect in 
reducing the number of estrogen-receptor positive tumors. 
	[Slide]
	So, overall we would conclude from our review that 
there was a significant reduction in the number of breast 
cancer cases with tamoxifen regardless of the subgroup.  At 
the beginning of this trial and throughout the conduct of 
the study there had always been concern about use of 
tamoxifen in younger women.  We looked at them specifically.  
We did not see an excess number of cases in young women, nor 
did we see more aggressive appearance to the tumors in young 
women. 
	We would say that at this point there is an 
unknown effect in women of color, simply based on the small 
number of participants in this trial; again, that it appears 
to have an effect on ER-positive but not ER-negative breast 
cancers; and we would like to point out that we did not see 
an excess number of ER-negative cases. 
	[Slide]
	As you have already heard, it is most effective 
against cancers that were earlier in the course of their 
development.  You saw this information from NSABP, not in my 
presentation, but we also independently calculated the time 
to event.  We did it by 6-month intervals, and there was a 
reduction in the number of cases diagnosed in the first 6 
months and then within every 6-month block afterwards, 
including at the 60-month time point. 
	[Slide]
	In terms of the non-invasive breast cancer 
endpoint, NSABP reported 59 cases on placebo and 31 on 
tamoxifen.  When we reviewed the case report forms for these 
participants, 28 of these non-invasive cancers were actually 
diagnoses of LCIS, 21 on the placebo arm and 7 on tamoxifen.  
An additional 2 cases consisted of atypical hyperplasia 
without a component of invasive or non-invasive cancer, 1 on 
each arm. 
	[Slide]
	When we looked at the women who had been diagnosed 
with LCIS during the course of the study, 12/28 women on 
placebo and 6/7 on tamoxifen had a prior diagnosis of LCIS 
as part of their eligibility criteria to enter the study.  
The seventh participant on the tamoxifen arm had a diagnosis 
of atypical lobular hyperplasia at entry.  When she 
subsequently had her biopsy and had those slides read in 
conjunction with her prior biopsy it was felt that both 
specimens met the criteria for LCIS. 
	[Slide]
	We would disagree with the inclusion of LCIS as a 
non-invasive breast cancer event for the following reasons:  
LCIS is commonly considered to be a marker lesion rather 
than a precursor.  It has a high incidence of multifocality 
and multicentricity, and sequential diagnoses of LCIS do not 
change the level of risk that is conveyed by the first 
diagnosis.  There are a number of options for LCIS, 
including now, we believe, tamoxifen on the basis of the 
results of this study.  Finally, our strongest reason is 
that we would not use entry criteria as a subsequent 
efficacy endpoint.
	[Slide]
	For those reasons, we would instead re-categorize 
this grouping as DCIS alone.  When we do that, there are 35 
cases on placebo and 23 on tamoxifen.  Remember that there 
were 2 cases on placebo that we had reassigned into the 
invasive category.  Overall, this showed a 34 percent 
reduction in risk.  Calculation of a p value on this 
difference was 0.12.
	[Slide]
	In terms of fractures, it was thought that 
tamoxifen would prevent the incidence of fractures.  In the 
protocol the hip and Colles' fractures were the 
prospectively designated sites. 
	The protocol discussed the inclusion of spine 
fractures but excluded them because of the following 
reasons:  There is no agreed-upon definition of a vertebral 
fracture.  Many vertebral fractures are unknown to the 
patient, and the methods for determining vertebral fractures 
are costly and are not reproducible.  We agree with the 
protocol-defined reasons for excluding spine fractures and 
we would not consider them to be a reproducible efficacy 
endpoint.  
	[Slide]
	We made this point before, that all fractures were 
reported, not simply the first event, and we didn't have any 
information on concomitant use of medications that would 
affect osteoporosis risk, with the exception of calcium. 
	[Slide]
	Overall, there does appear to be a reduction in 
the number of hip fractures with tamoxifen.  There were 20 
on placebo and 9 on tamoxifen.  Reductions were seen in 
women under age 50 and over age 50, although we would point 
out that there were very few fractures, 4 on placebo and 
none on tamoxifen, that occurred in younger women. 
	The final FDA assessment of the Colles' fractures 
is pending review.  NSABP is currently reviewing the radial 
fractures that occurred on study and is going to provide us 
with the final list that we will review. 
	We would simply add this particular caveat, that 
the fracture data in this study were derived from this sole 
study as a secondary endpoint and that, while it is very 
important to include this in the risk-benefit assessment of 
using tamoxifen for prevention of breast cancer, we would 
not consider this to be an independent indication for 
tamoxifen therapy solely for osteoporosis prevention.
	[Slide]
	In terms of deaths on study, as you have already 
heard, they were relatively well balanced between the arms.  
We did not see any difference either in the number of breast 
cancer related deaths on each arm.  When we reviewed case 
report forms, there was 1 case that had been coded as death 
from non-malignant respiratory disease and we found that to 
represent death from a pulmonary embolism in a tamoxifen 
participant.  NSABP agreed with that assessment and, in 
fact, their database has already been updated to reflect 
this finding. 
	[Slide]
	Turning now to endometrial cancer, this table 
summarizes the women who developed endometrial cancer.  This 
lists the number of cases by age at randomization.  As you 
have already heard, all of these cases except 1 represented 
FIGO stage I disease.  This slide breaks it by FIGO stage A, 
B and C, as you can see.  In the next slide I would like to 
make two additional points about the last two rows on this 
slide. 
	[Slide]
	First, there were 6 women, 1 on placebo and 5 on 
tamoxifen, who by case report form review had no signs or 
symptoms that suggested that they had endometrial cancer at 
the time of their diagnosis.  Of these asymptomatic women, 
4/6 were diagnosed during a routine endometrial sampling.  
The sampling was performed on schedule and it turned out to 
be positive for cancer.  The other 2 women were found to 
have complex atypical hyperplasia and at their institution 
that was treated by hysterectomy.  Then in the pathology 
specimen of the uterus cancer was found incidentally. 
	In the second to last row of the previous table, 
we would like to point out that 6 women on tamoxifen and 1 
on placebo received postoperative irradiation in addition to 
their surgical procedure for FIGO stage IB disease.  I 
mention this only because it does have some additional 
implications for complications of therapy, both short term 
and long term, and should be considered by women who are 
thinking about using tamoxifen for prevention. 
	[Slide]
	We have seen some information already suggesting 
that women under the age of 50 had no excess risk of 
endometrial cancer on tamoxifen compared to placebo.  The 
average annual hazard rate for these women was calculated at 
1.10.  That rate is somewhat higher than that reported by 
SEER data.  I think that you can make the argument that 
women at risk for breast cancer also have risk factors that 
make them at increased risk for endometrial cancer, and SEER 
data may not be the best comparative rate.  A better group, 
we thought, might be the placebo group in B-14.  For women 
under age 50 that annual hazard rate was calculated to be 
0.2, still lower than what was seen in this study. 
	[Slide]
	But we also noted that if you changed the age 
grouping you could affect the case distribution.  Here is 
endometrial cancer by age at randomization, as you have 
already heard, reported from NSABP.  If you changed this 
category by 1 and instead of saying less than or equal to 49 
you say less than or equal to 50, you do see a difference.  
There is a slight excess number of cases on the tamoxifen 
arm compared to placebo.  If you look at how old the 
participants were when they were diagnosed with the 
endometrial cancer, you can see again that the numbers of 
cases shift.  There are a few extra on tamoxifen but 
relatively few cases overall.  If you try to get at the 
actual biologic menopausal status at the time of the event, 
which was derived from case report form review, the numbers 
change again with a few extra cases on tamoxifen. 
	[Slide]
	There are several ways that you can interpret this 
data.  One would be to say that there is no added risk from 
tamoxifen with respect to endometrial cancer risk in young 
women.  I suppose you could also say that an increased risk 
of tamoxifen was masked in this study by an unusually high 
rate of endometrial cancer in the placebo group. 
	What we really think is the most logical 
explanation is this third one, that overall there were 
relatively few cases of endometrial cancer and that they 
don't really permit a detailed subset analysis that would 
give us a good idea of the relative risks in these groups. 
	[Slide]
	In terms of ischemic heart disease, when the study 
was started it was hoped that tamoxifen would reduce the 
number of ischemic heart events but, as you have already 
heard, there was overall no difference between the treatment 
arms.  This population was generally healthy.  Many of the 
women really had very few or insignificant risk factors for 
cardiovascular disease. 
	In the protocol it was originally written that 
approximately 10,000 postmenopausal women were required to 
demonstrate a cardiovascular benefit and a little over 8000 
were enrolled.  We discussed this point specifically with 
Dr. Costantino who pointed out that certainly you can't 
completely exclude a benefit of tamoxifen.  On the other 
hand, this trial did not demonstrate any effect of 
tamoxifen, and you might have leaned a little bit more on 
this interpretation if you had seen even a trend towards an 
improvement on tamoxifen.  So, we would leave that where it 
is.  No benefit was seen and I think that is the only 
conclusion that we can draw about that point. 
	[Slide]
	In terms of stroke, again 1 event per participant 
was counted and the worst event, TIA or stroke, was counted 
in the database.  On our case report form review though 
there was 1 participant on the placebo arm and 2 on 
tamoxifen who each had 2 separate stroke events. 
	Overall, there were 24 strokes reported on 
placebo, 34 on tamoxifen, and relatively few of these women 
were under age 50 at the time of the event.  The majority 
were postmenopausal.  Three were fatal on placebo, 4 were 
fatal on tamoxifen.  We wondered whether the excess risk on 
the tamoxifen arm could be related to the known increased 
thrombogenic properties of the drug. 
	[Slide]
	As you know, there were other thromboembolic 
events noted in the course of the study.  With deep vein 
thrombosis there were 19 cases on placebo and 30 on 
tamoxifen.  One participant who was randomized to placebo 
had a DVT while receiving open-label tamoxifen.  She had 
subsequently developed breast cancer and was being treated 
with tamoxifen.  She is appropriately listed on the placebo 
arm in the intent-to-treat analysis but I would just point 
out that her event occurred on the drug of interest. 
	[Slide]
	The sponsor, again, presented data for the 
diagnosis of deep vein thrombosis by age at randomization.  
If, instead, you look at the deep vein thrombosis incidence 
by the actual age of event, you can see that these risk 
ratios are really approximately the same, about 1.5 or so 
for the whole population or for either subset of women by 
age. 
	[Slide]
	Our conclusion looking at this is that the 
relative risk for DVT is likely to be the same in younger 
and older women, although the absolute number of events is 
greater in older women.
	[Slide]
	One thing that I would like to point out, again 
from our review of the case report forms, is that 
unfortunately there were delays in the diagnosis of DVT of 
up to 4 weeks.  This was not due to any laxity in terms of 
monitoring but many of the participants had these vents 
between the scheduled visits.  They then went to their local 
provider or emergency room and did not always tell the 
treating physician that they were part of the tamoxifen 
study.  So they were managed potentially more conservatively 
than they might have been.  I think this also has 
implications for patient education if the drug is approved.
	[Slide]
	In terms of PE, as we have already mentioned, 
there were originally 6 reported on placebo and 17 on 
tamoxifen, 2 fatal.  The third fatal case was added here for 
a total of 18 and 3.  If one looks at the time of occurrence 
of the event, all except 1 which was on the placebo arm, 
occurred in women who were over the age of 50. 
	[Slide]
	I wanted to make some comments about 
thromboembolic events as a whole.  The reported numbers that 
we have talked about don't count multiple events in the same 
participant.  On the placebo arm there were 4 women who had 
2 or more deep vein thromboses, and there were 3 who 
presented with simultaneous PE and DVT, not an unusual 
occurrence in general medical practice.  On the tamoxifen 
arm 1 woman had a recurrent DVT, 3 women presented with 
simultaneous deep vein thrombosis and pulmonary embolus, and 
there was 1 woman who presented with a DVT and PE that was 
separated by a 3-month period of adequate anticoagulation 
for these events. 
	[Slide]
	There were also complications of these events that 
occurred.  The ones that we saw in the case report forms 
were all on the tamoxifen arm.  Two women who had DVTs had 
subsequent chronic venous insufficiency.  One woman 
developed a GI bleed in the course of her anticoagulation 
for her event.  She required 5 units of packed red cells and 
fresh frozen plasma.  So, it was a significant bleed.  One 
woman on tamoxifen presented with a very large PE that had 
blocked the perfusion to her right lung.  She was treated 
with intra-arterial urokinase, was able to have blood flow 
restored to her lung and was then placed on conventional 
anticoagulation.  She then developed a large retroperitoneal 
bleed and required a filter placement for definitive 
treatment.
	[Slide]
	There were also some other thrombotic events that 
occurred.  Two premenopausal healthy women randomized to 
tamoxifen experienced retinal vein occlusions.  One of these 
occurred while the participant was on study drug and the 
other occurred when she had discontinued study drug for more 
than a year.  One of these women had some permanent 
impairment in her vision. 
	When we looked at the women overall with 
thromboembolic events, smoking and obesity were contributing 
factors but they didn't account for all of the risk.  This 
echoes one of the questions from the committee, 
investigators in the past have tried to look at the 
underlying etiology of the coagulation defect that is 
associated with tamoxifen.  Nothing definite has been found, 
but it would be helpful, we think, to evaluate this again in 
these participants.  Certainly, if a subgroup of women could 
be identified who are at risk that would significantly help 
many women in their assessment of the risk-benefit ratio. 
	[Slide]
	Our conclusions looking at thromboembolic events 
would be that all women on tamoxifen, regardless of their 
age, are at increased risk for thromboembolism.  I think it 
is important to point out to women that if they have one 
event they are at risk for a second related event, and that 
they may also be at risk for complications of therapy, and 
that factors that may predispose to thromboembolic events 
should be examined. 
	[Slide]
	I don't want to repeat the information on 
cataracts.  You have already heard that presented by the 
sponsor. 
	[Slide]
	In terms of other ophthalmologic events on study, 
I have already discussed the 2 retinal vein occlusions.  
NSABP sent us their data on incidence of macular 
degeneration, which was comparable between the 2 arms.  
There was no other information that was systematically 
collected on the effect of tamoxifen on other eye events.  
Again, as came out during the question and answer period 
earlier, the participants were not required to have regular 
eye exams. 
	The decision for this was made on the basis of the 
B-14 data which was derived from approximately 300 women 
involved in B-14 who volunteered for this sub-study.  
However, we would point out that overall the incidence of 
these eye events is rare, and it is possible that B-14 has 
not fully captured all of these eye events. 
	[Slide]
	We have spent a lot of time talking about very 
serious and potentially life-threatening effects of 
tamoxifen.  I think it is important to spend a few minutes 
talking about the day-to-day adverse events such as hot 
flashes and vaginal discharge.  Overall, as predicted by the 
known side effects of tamoxifen, women on tamoxifen had a 
higher percentage of hot flashes and vaginal discharge, and 
were also more likely to have level 3 or level 4 events.  As 
I said, these were the primary reasons that women stopped 
therapy, and the most troublesome effects on a day-to-day 
basis.  So, I think it is worth looking at those numbers. 
	[Slide]
	In terms of other events, there was no difference 
in the incidence of vaginal bleeding or vaginal dryness 
between the 2 arms, and overall in terms of the laboratory 
abnormalities, relatively few grade 3 and 4 abnormalities 
were seen and, as you can see here, there was really no 
significant difference overall between the 2 arms.  There 
had been reports of tamoxifen's effect on lipid profiles.  
Lipids were collected only at baseline, not throughout the 
course of the study, so we can't comment on that. 
	[Slide]
	Quality of life was measured during the study.  A 
medical outcome scale was used for general physical 
functioning.  There was a sexual activity item and a 
depression scale. 
	I am going to talk more about the depression scale 
in a minute so I would like to spend just a little time 
describing what that was.  This was a 20-item inventory of 
statements, and participants were asked to rate the number 
of occurrences that they had during the past week.  These 
were then translated into a numeric score and were 
categorized in groups.  A score of less than or equal to 15 
was a normal score.  This was collected at each separate 
visit. 
	We did not ask NSABP to submit the primary data 
for this.  Instead, we asked them to submit their analyses, 
and there was no difference at all between the 2 treatment 
arms for any of these 3 categories.  The curves were 
virtually superimposable.  This was reviewed by  Tony 
Kontsoukos, our statistician, and he could not find any 
problem with the analyses as presented.
	[Slide]
	We did review the depression data in more detail 
though because of past reports that tamoxifen might be 
associated with an effect on depression.  In addition to the 
depression scores that I have already discussed, depression 
was also assessed with a neuro-mood common toxicity criteria 
reporting.  When the participants came, in addition to the 
20-item list that was translated into the depression score, 
they also filled out some additional paperwork that 
reflected their mood.  This data was also forwarded to the 
NSABP.  The study coordinators were able to translate this 
into a CTC grade as non, mild, moderate, severe, suicidal or 
death. 
	What we did, we looked at the depression scores 
and then we looked at the participant assessment of mood by 
the CTC grades, and then we also looked at events that we 
derived from our case report form review. 
	[Slide]
	So, in this very informal analysis based simply on 
selected cases that we had, this is what we found.  Out of 
the 69 women who were reported as having severe depression 
and, again, equally distributed between the 2 arms, 18 of 
those had normal depression scores.  There were 46 women who 
were listed as being suicidal on study, again comparable, 
and 4 of them had normal scores.  There were 3 women who did 
commit suicide on study, 1 on placebo and 2 on tamoxifen.  
Two of them had grade 4 scores but 1 had a grade 1 score. 
	[Slide]
	As I said, from this very informal analysis we 
would just like to make the following points, and some of 
them are obvious:  The scores are likely to be accurate only 
if they can be obtained at the time of maximum distress.  
With women being followed every 6 months, it is likely that 
you are going to miss that time point and then get reporting 
of events in the past. 
	The other thing that we noticed is that when we 
looked at the case report forms, women reported the 
prescription of antidepressant medications at the time that 
they had scores of grade 0-2.  There are two possible ways 
to interpret this.  One is that our usual system of 
reporting a grade 3-4 event may underestimate a clinically 
important change in mood that warrants the prescription of 
these medications, or that the use of these medications 
confounds the scoring system, that these women start 
antidepressant therapy, feel much better and when they come 
in their scores look fine. 
	So, overall we would say that while P-1 doesn't 
show any effect of tamoxifen on depression, we would simply 
point out that perhaps this was not the best way to capture 
this information, and that it may still be unknown. 
	[Slide]
	In the course of the review also 2 European 
studies that were negative trials for tamoxifen for 
prevention of breast cancer were reported.  We would like to 
comment briefly on these.  We did not have primary data for 
review.  This is based on our reading of The Lancet 
analyses. 
	The Italian breast cancer prevention study really 
did not enter women who were at high risk for breast cancer.  
It was, instead, designed to exclude women who were at high 
risk for toxicity from tamoxifen.  So, they were eligible 
only if they had a hysterectomy, and there was another long 
list of exclusion criteria, and they made no effort to 
actually enrich for women who might be at increased risk for 
breast cancer itself.  There was a high drop-out rate in the 
trial that was not considered in the sample size 
calculation, as it was in the NSABP study, and, in fact, 
their monitoring committee closed the study early because of 
this reason.  Overall, the authors reported that there was a 
low statistical power to detect any difference between the 
arms. 
	[Slide]
	The other trial was the Royal Marsden study.  As 
you have already heard, Dr. Powles is here with us today.  
He will actually come to the podium after I have finished to 
make a few comments, and will be available for questions 
from the committee about his study.
	Based on my review of the published article, and 
not on his data -- he is the only one with the data, I would 
make these points.  The Royal Marsden study was designed 
initially to enter a high risk population of women.  It was 
hoped that it would be selected out to include women who 
were members of a hereditary breast and ovarian cancer 
family.  However, from my reading, I would think that the 
assumption of the baseline for breast cancer risk in this 
trial was inaccurate.
	There has been a lot of data published recently 
from a number of risk assessment centers looking at the 
incidence of mutations in women based on their family 
history.  These reviews have suggested that if you use only 
a breast cancer family history that you are likely to see 
mutation in only about 20 percent of those patients.  You 
can increase the likelihood of seeing a mutation if you also 
include family history of ovarian cancer, or if you extent 
out your family history and, instead of looking simply at 
first degree relatives as was done in the Royal Marsden 
study, you take an extended family history.  So, overall, I 
think although it was intended to enroll women at higher 
risk, those women were actually at lower risk than 
anticipated. 
	The rate of non-compliance was not considered in 
the sample size calculations.  I think these are the primary 
reasons for the negative outcome.  These are additional 
possibilities -- younger women are likely to have slightly 
higher rate of ER-negative cancers compared to older women, 
and we have already seen that tamoxifen is not effective, we 
don't think, against ER-negative cancer prevention.  Hormone 
replacement therapy was permitted in the study and about 41 
percent of the women in the trial used hormone therapy at 
some point in the study and that may be a confounding 
factor.  Again, Dr. Powles' input on these issues would be 
appreciated. 
	[Slide]
	So what can we say overall about the risks and 
benefits of tamoxifen based on the P-1 study?  Well, I 
believe that form this trial it has been clearly 
demonstrated in the subgroups, with the follow-up we have, 
that there were fewer cases of invasive breast cancer with 
tamoxifen.  It reduced the number of cases of ductal 
carcinoma in situ, not significantly but there were 
certainly fewer cases.  Again, it may prevent hip and 
Colles' fractures. 
	[Slide]
	We think that there was an unknown effect, based 
on these trial results, in women of color because of the few 
number of women entered.  There was no information here 
about women with BRCA 1 and 2 mutations.  As you have heard, 
the NSABP was planning to assay the serum samples and to 
look for mutations, and those data are going to be awaited 
with interest by everyone, by the medical community and FDA.
	I have included women with known DCIS in this 
column.  Again, there are early reports that show a benefit 
with tamoxifen in women with DCIS but, as Dr. Wolmark said, 
that is pending final review of the NSABP studies that were 
specifically designed to address this question. 
	We think simply based on the follow-up data 
available here that we probably still have an unknown effect 
of tamoxifen on depression, and a non-cataract ophthalmic 
toxicity. 
	[Slide]
	There was no effect that was observed on ischemic 
heart disease, on death from all causes.  We also agree that 
there was no difference in the incidence of other cancers.  
Again, from our analysis we did not see that LCIS was 
prevented. 
	[Slide]
	Finally, I think we have spent a lot of time 
talking about the risks.  Tamoxifen increased the risk of 
endometrial cancer, of DVT and PE, stroke, cataract 
formation and the need for cataract surgery, and hot flashes 
and vaginal discharge. 
	[Slide]
	It is important that we all keep in mind what the 
limitations of tamoxifen are.  It does not eliminate breast 
cancer risk, as we have talked about previously.  It also 
does not guarantee that if a breast cancer occurs it will be 
diagnosed at an early stage.  It does not affect ER negative 
or larger tumors. 
	[Slide]
	There are additional complications to tamoxifen 
therapy, other than the listed risks.  Again, remember that 
some of these early stage endometrial cancers required 
irradiation therapy in addition to surgery, with potential 
additional complications; that thromboembolic disease may 
involve the brain, lung, leg and eye.  It can increase the 
risk of a second event, and there may be complications from 
treating these events. 
	[Slide]
	We think that all of these findings have labeling 
implications, and we have asked some of these in specific 
questions to the committee.  Women on tamoxifen, regardless 
of age, should have regular breast exams, mammograms and 
gynecologic evaluations.  We would agree that endometrial 
sampling detected endometrial cancer rarely.  There is a 
specific question to the committee on this point.  We also 
believe that women taking tamoxifen should seek prompt 
medical attention for any signs or symptoms of cancers or 
thromboembolic events. 
	There is a question to the committee about whether 
women on tamoxifen should undergo yearly eye exams based on 
the cataract data and some of the other issues that we 
discussed. 
	Most importantly, we believe that women who choose 
to take tamoxifen should inform all care providers, no 
matter what they are being evaluated for, that they take the 
drug.  We would also say that women with a history of DVT, 
PE or coagulopathy should not take tamoxifen.  This was an 
exclusion criterion for the P-1 study.  And, labeling should 
provide information about individual risks and benefits.  
One point that also may seem obvious but I think is worth 
mentioning is that a premenopausal woman who starts therapy 
may become postmenopausal in the course of her treatment, 
and that may result in a change in her risk-benefit 
assessment and that should be kept in mind. 
	[Slide]
	How do we put this in perspective with the 
negative European trials?  Although the European trials 
reported negative results, we believe that there were design 
differences that resulted in lower risk populations being 
entered into those studies.  Overall, the size, the 
statistical power and the internal consistency of P-1, we 
think, make its results robust and believable, and we also 
believe that the results are consistent with all of the 
other published reports of the ability of tamoxifen in the 
realm of prevention, most notably preventing contralateral 
breast cancer.  So, we would feel that the weight of the 
evidence favors what was observed in P-1. 
	[Slide]
	In conclusion, tamoxifen for breast cancer was 
effective in reducing the incidence.  The reduction in 
breast cancer incidence for most women appear to outweigh 
the incidence of serious adverse events but, as we have 
already discussed, it is extremely important to have an 
individual risk-benefit assessment and that, hopefully, that 
can be conveyed in labeling as well as in additional 
educational tools to allow women to make a truly informed 
decision about whether to use this drug if it is approved. 
	Thank you.  What I would like to do now is to 
introduce Dr. Powles who has a few comments, and then both 
of us will be available for questions.
Comments on the Royal Marsden Study
	DR. POWLES:  I am grateful -- at least I am not 
sure I am grateful to have the opportunity to discuss 
briefly the conflict in the results that occurred between 
our own program and the NSABP program. 
	I have to say right from the word go that I 
thought 12 years ago or 13 years ago when we started the 
tamoxifen prevention that if I was going to be here, I would 
be here presenting the results of a positive trial on 
tamoxifen and I am as surprised as anybody that we actually 
got a negative result at this stage.
	Secondly, I would like to make quite clear that I 
am absolutely sure that the effect of tamoxifen on the early 
incidence of breast cancer in healthy women which has been 
shown by the NSABP is real.  The problem is what is the 
conflict between the two results.
	Susan has mentioned the various problems that may 
arise.  The first is that there is clearly a difference in 
the study population.  Our women are younger.  Our women are 
more likely to have a stronger family history.  They are 
more likely to be premenopausal.  And, what we have done, in 
spite of what Susan said, is a complete pedigree analysis of 
all of the women in our program, all 2500 women, in order to 
evaluate not just the incidence of primary breast cancer but 
the age at onset of the primary breast cancer, which is 
important, second degree relatives with breast cancer, and 
the presence of bilateral breast cancer and the presence of 
other cancers. 
	So, we have been able to estimate using pedigree 
analysis, and using the Klaus model the likelihood of high 
risk genes within our own program.  Our estimate at this 
time is that about 36 percent of the women in the Marsden 
program are likely to have inherited a high risk breast 
cancer predisposing gene.  What is more important is that 60 
percent of the women who developed breast cancer at this 
time are likely to have inherited a high risk breast cancer 
predisposing gene.  This is going to be substantially more 
than the percentages in the NSABP program, as best as we can 
estimate it from the figures of the data that we already 
have. 
	So, I think a major difference between our program 
and the NSABP program relates to the study population, and I 
think it could well relate to the likelihood of inheriting a 
high risk gene. 
	The second point that Susan mentioned was the 
question of compliance.  In fact, our compliance has been 
higher than we estimated when we originally did our power 
calculations.  The estimate for 5 years was going to be for 
70 percent and, in fact, looking at the time of use of 
tamoxifen within our program, at 3 years we got an 83 
percent compliance for tamoxifen and at 5 years we got a 79 
percent.  I think this is about as high as you are likely to 
get, and this represents a substantial intervention of 
tamoxifen in half of 2500 healthy women, 1250 women, and, to 
my mind, that amount of exposure to tamoxifen with what is 
going to be a 50 percent effect -- we would anticipate on 
that compliance that we would be able to see that effect.
	The third point that was raised was about the use 
of hormone replacement therapy.  We allowed the use of 
hormone replacement therapy within our own program because 
we felt that denying the use of hormone replacement therapy, 
as you can see from the NSABP results where women would be 
withdrawn from the program if they took hormone replacement 
therapy, in itself would produce a bias if it was not 
matched.  And, 41  percent of our women at some stage have 
taken hormone replacement therapy.  But we are now 12 years 
into the program, and if we actually look at the amount of 
hormone replacement therapy that was used in conjunction 
with tamoxifen or placebo, there was only a 12.6 percent 
concomitant medication.  So, it is really a very small part 
of the program itself.
	The second thing is that we have been unable to 
identify any interaction between the use of hormone 
replacement therapy and tamoxifen on bone, on clotting 
factors and on cholesterol, and we have published this, and 
it, therefore, seems unlikely that this would occur in the 
effect on tumor cells.
	The third thing is that we can see no difference 
in the incidence of breast cancer for women on or off 
hormone replacement therapy who have ever had it or not had 
it.  In fact, if anything, there is a marginal effect for 
women who have had tamoxifen versus those who have not.  So, 
it is unlikely that we would have confounded our trial in 
order to make it negative. 
	Furthermore, the Italian trial has shown the only 
effect that they could see was the use of tamoxifen in women 
on hormone replacement therapy.  So, I think it is very 
unlikely that hormone replacement therapy could have 
confounded our trial in a way that would have made the trial 
negative. 
	The fourth point is whether the trial ever had the 
power to be able to show this effect.  We clearly are a 
small trial, although we are talking about 2500 healthy 
women from a single center, which must be one of the biggest 
single center trials that has ever been mounted on anything.  
We did do the power calculations in 1993 when we realized 
that the national program would not be able to start because 
it had not been approved by the Medical Research Council in 
England.  We did the power calculations then to estimate the 
numbers of women we would need, the compliance that we would 
expect on an intent-to-treat basis that would give us a 90 
percent power to detect a 50 percent reduction. 
	In fact, those power calculations were exactly 
right for the placebo.  We were within 1 cancer for the 
incidence of breast cancer, and it was exactly on point at 
the beginning of 1998 when we did our estimates.  There is 
only about a 10 percent chance that this trial is negative 
for statistical reasons.  In fact, what is more impressive 
is the fact that we can't see any difference at all in the 
incidence of breast cancer for tamoxifen or placebo.  There 
is not even a trend there. 
	With the Italian trial, that is also completely 
negative for a different population of women, and the 
chances of both trials being negative is less than 2 
percent.  I think probably the reason we are seeing these 
differences -- they can account for various things that may 
do this, but one of the main factors in my opinion probably 
is the fact that we are looking at different populations of 
women.
	As far as the power calculations go, the problem 
that we have is the problem of multiple outcomes, and this 
is shown with the power problem in relation to the NSABP 
trial.  In spite of what was said earlier, the primary 
objective of the NSABP trial in the original protocol was to 
test tamoxifen's effectiveness in preventing the occurrence 
of breast cancer and reducing mortality in breast cancer.  
So, it was originally designed and the power calculations 
were done for reduction and mortality.  It also wanted to 
look at heart mortality and bone fractures, and benefit-risk 
ratio as secondary aims. 
	The trial was stopped early when there were 239 
breast cancers.  At that time there were only 9 breast 
cancer deaths and 10 heart deaths.  So, there was never any 
hope that we were going to be able to look at one of the 
main features of the primary aim, which was mortality from 
breast cancer, because the trial was so powered to look at 
incidence of breast cancer that it wasn't going to allow the 
secondary outcomes to be seen. 
	I am obviously concerned that if everything we do 
in the future is going to be based on early incidence data, 
will it actually tell us much more than that about the 
prevention of breast cancer and, in particular, what the 
clinical benefits may be?  I am concerned because when we 
look at these results at the present time there are only 69 
breast cancers at 3.5 years median follow-up, and these are 
mostly estrogen-receptor positive cancers, less than 2 cm 
and no nodes or 1-3 nodes.  We would anticipate that there 
would be a cure rate for these 69 cancers of about 80-90 
percent.  This is particularly so because they are likely to 
be tamoxifen sensitive because they have been prevented from 
occurrence by tamoxifen.  To achieve this reduction in 69 
cancers, 6600 healthy women have received tamoxifen for an 
average of 4 years, and that, even with compliance, is about 
20,000 years of tamoxifen or 300 years for each what I would 
call good cancer that has been delayed or prevented.
	The question that we must ask in any prevention 
trial is would it have been easier to have treated the 69 
cancers versus the 6600 healthy women because prevention 
trials are a completely different dimension than treatment 
trials.  We are talking about treating huge numbers of 
healthy women in order to prevent small numbers of cancers. 
That is the issue that I am obviously concerned about.  I am 
not sure that at this stage we know enough to be able to say 
that prevention in many is better than treatment in a few. 
	In Europe, the Clinical Trials Committee is not 
satisfied that "prevention" has been proven to be 
beneficial, clinically beneficial.  We would wish to 
continue our trials to evaluate not just the incidence but 
all potential long-term benefits and risks that we can, the 
most important of which is obviously mortality from breast 
cancer.  Furthermore, because of the concerns we have about 
subgroups and high risk groups, the high risk genes and low 
risk genes categories, we would like to try to identify the 
subgroups of those who may or may not gain a benefit, 
especially the high risk young women who are likely to pay 
the long-term consequences if there are any problems with 
tamoxifen. 
	Approval of tamoxifen for prevention at this time 
implies that we know its use in healthy women is a clinical 
benefit and we know who gains that benefit.  And, I don't 
think we are there yet.  In spite of this early incidence 
data which I think is very encouraging, I am not satisfied 
that we have proven at this time that long-term use of 
tamoxifen in healthy women is likely to be beneficial over 
the risks.  We are talking about large numbers of healthy 
women and there are risks.
	Thank you. 
Questions from the Committee
	DR. DUTCHER:  Questions for the FDA and Dr. 
Powles?  Dr. Albain?
	DR. ALBAIN:  Yes, Dr. Powles, could you comment on 
your choice of duration of treatment in your trial of 8 
years of tamoxifen, in particular given the concern that 
durations beyond 5 years may, in fact, be adverse in terms 
of tamoxifen-stimulated growth?  How many women actually got 
8 years of tamoxifen? 
	DR. POWLES:  I think we must distinguish between 
the treatment trials and the prevention trials.  When we are 
doing treatment trials we are looking at cancer that is 
there that may go away and may come back.  With prevention 
we are looking at anti-promotion of estrogen by using an 
anti-estrogen, and the events of the initiation of the tumor 
can occur at any time. 
	We had to make a decision in 1991, because we 
started our trial in 1996, when we reached 5 years about 
whether we gave more than 5 years or not.  At that time it 
was agreed that we would continue to 8 years.  This was 
discussed with various bodies in the United Kingdom, and 
that was based on the fact that we were looking for 
anti-promotion of early cancers and not treatment. 
	I don't think the results of the adjuvant trials 
bear any relationship to anti-promotion.  They obviously do 
if you are only treating occult cancers. 
	DR. ALBAIN:  What percentage of your population 
took the full 8 years?
	DR. ASHLEY:  I am Sue Ashley.  I am a statistician 
at the Royal Marsden.  Sorry, I don't have the exact figures 
but I think it was around 160 on both tamoxifen and placebo 
who have completed 8 years of treatment at the moment. 
	DR. ALBAIN:  And these are women on active 
treatment?  In other words, they hadn't dropped out before 
that 8-year point.  Is there a percent that have already 
dropped out?
	DR. ASHLEY:  There is a percent who have already 
dropped out.  These are people who have continued for 8 
years.
	DR. ALBAIN:  What percentage have dropped out, and 
at what time points of treatment, do you know?
	DR. ASHLEY:  There was about a 17 percent drop-out 
in the first year of treatment.  After that there was very 
little drop-out on the tamoxifen arm. 
	DR. ALBAIN:  Thank you.  I also have a question 
for Dr. Honig.  Could you just clarify from your review of 
the data patient events, breast cancer events -- my 
understanding is they were reported as an event whether they 
were on study drug or off study.
	DR. HONIG:  That is correct.
	DR. ALBAIN:  Okay.
	DR. HONIG:  That was a mis-communication in my 
draft, the draft that went to ODAC while we were still 
communicating with the sponsor.  So, that was an error and, 
hopefully, was corrected in my slides.
	DR. ALBAIN:  Okay.  Then, the patients who had the 
DCIS event, were those patients continued on tamoxifen?
	DR. HONIG:  That also was clarified with NSABP.  
By protocol, they were supposed to continue on blinded 
therapy and that did not always occur.  I am trying to 
remember offhand the number of women who were unblinded.  
Jo, you may be able to help me out.  I think it was maybe 10 
or 12 per arm, a relatively small number compared to the 
total number of DSCIS events. 
	DR. ALBAIN:  So maybe I should ask the NSABP.  
Were patients with DCIS, for the most part, continued on 
their study drug?
	DR. HONIG:  Please clarify this, Jo, but it seemed 
like there was a group who stopped drug altogether and then 
there were some who were unblinded and who may have 
continued open-label? 
	DR. COSTANTINO:  As you indicated, there were many 
instances where, regardless of what the protocol stated, the 
physicians felt they needed to know this information, and if 
they insisted upon being unblinded, they were.  The exact 
proportion of women who actually stayed on therapy of the 
DCIS cases -- to be honest with you, I don't know the exact 
number but there were women who did and there were women who 
were unblinded and did not.  So. 
	DR. ALBAIN:  Would you comment on the rationale of 
continuing the drug in the face of the event? 
	DR. WICKERHAM:  I can comment on why the desire 
was to continue the blinded drug per protocol.  At the time 
the trial began, tamoxifen was not of known benefit for the 
treatment of DCIS.  We thought it appropriate to capture the 
event to try to maintain the therapy per protocol.  As Dr. 
Costantino said, the majority appeared to do that but there 
were cases where either the patient or the physician 
demanded that the patient be unblinded. 
	DR. DUTCHER:  Dr. Sledge?
	DR. SLEDGE:  Dr. Powles, you are basically telling 
us that it is too early to know.  Could you give us your 
wisdom in terms of, first, how long you think this trial 
does need to be followed before we have data that would 
convince you and, secondly, what specific endpoints would 
convince you?
	DR. POWLES:  Yes, I found a reference to a paper 
that I wrote in 1988, I think it was, where we were looking 
at how long it took for breast cancers to develop.  We know, 
for example, from the nuclear explosions in Japan that the 
increased incidence of breast cancer doesn't start until 14 
years after irradiation and it needs endocrine promotion 
with estrogen. 
	So, in terms of interfering with estrogen 
promotion, we made estimations then, which we published, 
that we felt that it would take 10-15 years to really know 
what you were doing in terms of preventing breast cancer by 
using tamoxifen.
	Now, the thing that was encouraging is that we 
were obviously going to have a positive effect on the early 
incidence of breast cancer by treating subclinical disease, 
and because that went the right way we estimated that what 
would happen is that you would have 2 curves that started to 
go apart and they would continue to go apart, to begin with 
because you are treating breast cancers, some of which may 
or may not come back, and later on because you are 
preventing breast cancers. 
	What is more important is that most breast cancers 
are likely to be estrogen-receptor positive very early on in 
their process.  They are arising from a breast cell that is 
endocrine dependent, and they will use their receptor 
positivity with time.  So, by the time they present 
clinically only 18 percent of them are likely to be 
estrogen-receptor positive and only 50 percent of them have 
a functional estrogen receptor. 
	What we don't know is when we are giving tamoxifen 
early on in the natural history of breast cancer we could 
actually be preventing a 100 percent of the breast cancers.  
This is why long-term incidence data and long-term mortality 
data was going to be very important in terms of telling us 
what was going to be happening in the prevention scenario. 
	I can't emphasize too strongly that we are 
encouraged by this reduction in early incidence, but I still 
don't think it is telling us very much about the long-term 
prevention of breast cancer, which is what we need to know 
before we start getting on to the next agents, the tamoxifen 
look-alikes. 
	DR. SLEDGE:  So, again, I am sorry --
	DR. POWLES:  Ten to 15 years of follow-up is what 
I think you need before you really know what is happening.
	DR. SLEDGE:  Thank you. 
	DR. DUTCHER:  Dr. Margolin?
	DR. MARGOLIN:  I have a question about the data 
from what you call women of color.  First of all, is that 
African-American only or does that include Latinos, 
Filipinos?
	DR. HONIG:  A subset were African-American and the 
others were simply listed as "other" with no racial 
breakdown.
	DR. MARGOLIN:  If you look at the chart we got 
this morning about the effect of tamoxifen in ER-positive 
tumors, it is about a 67 percent reduction, with the others 
being equivalent.  Just arithmetically, there is about a 
2-fold increase, 6 versus 3, the wrong way in women of 
color.  But you didn't tell us whether those patients 
developed ER-negative tumors, in which case the data are 
just a wash.
	DR. HONIG:  No, they were all over the map.  We 
specifically looked at ER status, and I don't have those 
numbers with me although I think they are in my review, and 
they were not all ER negative and they were sort of a 
mixture.  I think of 3 cases 1 was ER positive, 1 was I 
think a mix.  Jo, do you have that data? 
	DR. COSTANTINO:  Yes, of the 9 cases which you 
were referring to, actually 7 were in Afro-Americans.  Among 
those 7, there were 3 ER-positive cases, 2 in the placebo 
arm and 1 in the tamoxifen arm.  So, if you limit yourself 
to the ER, it went the right away but the numbers are very 
small. 
	DR. DUTCHER:  Dr. Schilsky?
	DR. SCHILSKY:  I have a question for Dr. Powles in 
follow-up to Dr. Sledge's question.  I take your comments 
very seriously although they are reminiscent of comments 
that were made, I guess, in the 1970s with the introduction 
of adjuvant chemotherapy when lots of questions were raised 
about how many women should get adjuvant chemotherapy to 
prevent the recurrence of breast cancer in just a few, and 
it is a similar type of argument that you have made now.  I 
am concerned, I suppose, about the need to wait 10-15 more 
years to have definitive information, and whether or not 
such information could be available from the NSABP trial in 
view of the fact that so many women on the placebo arm are 
now likely to cross over to receive tamoxifen. 
	So, I suppose my question is do you feel that the 
NSABP, as it continues to mature, will be able to provide 
the definitive information that you are looking for, or are 
there other trials that are ongoing that will be able to 
provide that information relatively soon?
	DR. POWLES:  Yes, I think I need to make it clear 
that there are two different levels of the question.  One is 
if you really want to know what is happening in prevention 
you would have to wait 15 years, say, for incidence data.  
We know how useful, for example, the adjuvant data is, not 
just the 2- or 3-year data but the 5-year, the 10-year data.  
I mean, think what a disaster it would have been if we had 
given tamoxifen to everybody 3 years into the adjuvant 
trials and we didn't really know what was happening.  This 
is the same sort of situation here. 
	What I think the caveat is, as far as it goes with 
the prevention programs, we won't have to wait 15 years, 
although one would like to, because you are going to be 
looking at other endpoints and other outcomes, and the like.  
I would guess that in order to get sufficient information, 
in my opinion, if the NSABP hadn't been unblinded we would 
probably have been in a position with the European trials 
and with the NSABP to be getting meaningful answers on 
clinical benefits in the prevention scenario by the year 
2000, 2005.  That would have been something that we would 
have then built on for the next generation of 
anti-estrogens. 
	As far as the trial goes now, I don't know how 
much information you can get, now that it has been unblinded 
and now that tamoxifen and raloxifene will be offered in the 
control arm.  I don't know how much information we will get.  
I suspect not very much. 
	DR. DUTCHER:  Dr. Honig, you made a fairly strong 
series of statements about the thromboembolic events.  How 
many of those people actually had or soon after had 
developed cancer?
	DR. HONIG:  You mean the thromboembolic events in 
cancer patients in particular?  That is a good point and, 
without looking at my notes, relatively fewer than developed 
cancer.  Is that correct from your recollection, Jo?  The 
patients with DVT and PE?  I should say specifically breast 
cancer.  We looked for any cancer as a contributing factor 
to underlying clotting and there were certainly people who 
had procedures with general anesthesia; there were people 
who had long trips; there were people who were diagnosed 
with cancer.  But all of that did not account for all of the 
clotting events. 
	DR. DUTCHER:  Dr. Simon?
	DR. SIMON:  I have a couple of questions for Dr. 
Honig.  You said you looked at a variety of subsets for 
examining the relative effect of tamoxifen on lowering the 
risk of invasive breast cancer.  Did you look at women over 
60 who had a relative risk less than 2, or women over 60 who 
had a relative risk of 2-5?
	DR. HONIG:  We didn't have the information 
categorized by relative risk, and we didn't have the Gail 
model until I think the first or second week in August and 
we really haven't run any of those calculations.  But what 
we did, we looked at the individual risk factors which, 
granted, is not the same as the Gail model but, anyway, we 
looked at the various groupings, say, of age at menarche, 
first live birth, family history -- those sorts of things, 
and ran a series of queries --
	DR. SIMON:  That is a problematic way of doing it.  
In other words, if you need risk factors to get on study, 
then to look at those univariately is all confounded because 
those who don't have this one have something else.
	DR. HONIG:  Right.
	DR. SIMON:  So, you tend not to see anything.
	DR. HONIG:  Exactly.  I mean, we didn't have the 
disc so we were looking to see if, by eyeball, we could see 
if there were one factor that was driving everything.  In 
fact, there wasn't.  I think, as you say, it is the 
combination of risks, and there are many, many combinations.
	DR. SIMON:  I have a couple of other questions.  
You showed some data categorizing endometrial cancer cases 
based on woman's age, and you defined the age in a couple of 
different ways.  It looked, actually, fairly striking to me 
that the increased risk of endometrial cancer was greatest 
for women over 50.  You wound up concluding that you didn't 
have enough data to make any conclusion.  Did you do a 
statistical analysis on that?
	DR. HONIG:  We would say that, you know, you can 
frame shift everything depending on how you assign the 
cases, and that you get slightly different outcomes and 
that, yes, it is true most of the cases were in 
postmenopausal women but --
	DR. SIMON:  I mean, you got different numbers and 
the numbers change but in all of the ways you presented it, 
it looked like there were many more cases of endometrial 
cancer in the tamoxifen group.  The excess cases of 
endometrial cancer in the tamoxifen group relative to the 
placebo group always seemed to be concentrated in the older 
age group.
	DR. HONIG:  Yes.  I mean, that is true.  We think 
that most of them were in excess in the older group but to 
say that younger women are completely immune and that they 
have no risk other than the general population, we don't 
feel confident saying. 
	DR. SIMON:  The other thing that I guess I was 
surprised about is you showed data on number of events of 
invasive breast cancer after stopping the study drug, either 
tamoxifen or placebo, and I don't remember the exact numbers 
but I think it was something like 34 --
	DR. HONIG:  I think 38 and 32. 
	DR. SIMON:  Something like that, 38 and 32.  But 
that was fairly striking to me because there were only 85 
cases of invasive breast cancer in the tamoxifen group.  So, 
38/85 versus 32/154 for placebo, that suggests to me that it 
is pretty striking, that the tamoxifen cases are tending to 
occur after discontinuation of the drug and the placebo 
cases are not. 
	DR. HONIG:  I think what we found is even if you 
took those cases out, the number diagnosed on study drug was 
still less for tamoxifen compared to the number on placebo, 
and if you stopped study drug you then continued to find 
breast cancers but at approximately the same rate in either 
arm.  We were not trying to make too fine a point, except it 
certainly would have been of interest if you had stopped 
tamoxifen and then suddenly saw a rebound number of cases 
that brought you right back up to baseline. 
	We didn't see that.  What we saw is that you get 
some reduction while you are on tamoxifen and then you 
continue on at the same rates.  I guess the question again 
is, you know, at follow-up would you still in 10 years see 
that same difference?  How long does the effect of tamoxifen 
last, and which of the cancers have you interfered with?  
You know, have you treated some early stage 1, etc?  I think 
those are all valid and open questions at this point with 
the follow-up that we have.
	DR. DUTCHER:  Dr. Schilsky, I cut you off.  I am 
sorry.
	DR. SCHILSKY:  No, that is okay.  I really just 
want to make a comment with respect to the risk for 
thromboembolic disease.  There is a substantial body of 
literature to suggest that women who clot while receiving 
hormone therapy or during pregnancy may be carriers of a 
mutation in the Factor V gene, called Factor V Leiden.  I 
think it would be important to look at whether women who 
clot on tamoxifen might also be carriers of Factor V Leiden 
because that would provide a relatively simple screening 
test to sort out those women who might be at greatest risk 
of developing thromboembolic complications while on 
tamoxifen.
	DR. HONIG:  Thank you.  I think that is one of our 
questions to the committee.
	DR. DUTCHER:  Miss Beaman?
	MS. BEAMAN:  Yes, the doctor did say a moment ago 
that these are healthy women and they are now possibly 
tamoxifen sensitive.  What exactly did you mean by that, and 
how might that affect future treatment for those women in 
particular?
	DR. POWLES:  That is an interesting question.  
Yes, I wasn't meaning that.  I meant that those who get the 
cancers are likely to be tamoxifen resistant if they have 
been on tamoxifen when they get their cancers.  So, they 
will lose the benefit that they would have from tamoxifen.  
I don't think I understood -- as far as the rest of the 
population, for women who don't get breast cancer, I think 
the issue there is what are the long-term effects of 
tamoxifen, particularly in young, healthy women going out to 
20, 25, and 30 years?  That is an issue that we can't fully 
address from the adjuvant trials at the moment.
	DR. DUTCHER:  I think what he said was that if 
they were not treated and they got cancer, it would be more 
likely to be a tamoxifen-sensitive cancer. 
	DR. POWLES:  Yes. 
	DR. DUTCHER:  Dr. Albain?
	DR. ALBAIN:  For Dr. Powles again.  Trevor, I have 
to come back to your 10-15 years follow-up and that we can't 
extrapolate from treatment trials.  Don't you think that we 
could perhaps still extrapolate from the overview data in 
B-14 that does have that 10-15-year follow-up on a solid 
persistence of the reduction in risk of contralateral breast 
cancers despite only receiving tamoxifen for 2-5 years? 
	DR. POWLES:  I have a real problem with 
contralateral breast cancer in its own right.  You know, of 
all of the groups that we are looking at, populations of 
women that may be the same or different, second cancers are 
likely to be a subgroup that is special in many ways.  
Therefore, I have no problem saying that an indication for 
use of tamoxifen in a woman who has had breast cancer is 
prevention of her second breast cancer.  But taking that to 
a healthy woman and saying the same thing works in a woman 
who has never had breast cancer is a big step and you have 
to be sure that you are talking about the same biology.
	DR. DUTCHER:  Dr. Margolin?
	DR. MARGOLIN:  Just a comment to follow-up on 
that, I think in that trial also we had a very favorable 
group of patients who were ER positive and node negative.  
It is a highly select group of patients. 
	DR. DUTCHER:  Dr. Raghavan?
	DR. RAGHAVAN:  Trev, I am still a little unclear 
about the difference between the 2 populations.  You sounded 
tremendously confident that you could identify differences, 
and I guess I missed the point.  So, I just want to go back 
to that.  You said you thought they were younger and had a 
stronger family history and they were more premenopausal.  
In the NSABP group 76 percent had relatives; 39 percent were 
49 or less and about 70 percent, I think, were less than 60.  
Can you flesh that out a little?
	DR. POWLES:  Yes, I think the big difference is 
that if you don't do a pedigree, if you just look at the 
family history risk itself, then you don't really identify 
the high risk gene population.  You can be as low as, say, 
something on the order of 20 percent of those women you 
might identify that would actually be BRCA 1 or BRCA 2 
positive based on just the breast cancer history.  You 
really need to do the full pedigree, and there are various 
models that have been established. 
	I can't be confident that there are differences 
between the Marsden and the NSABP because we can't do the 
pedigree analysis -- we can't, on the data we have on the 
NSABP data set.  All we can say is that we can look at just 
the numbers of first degree relatives they have with breast 
cancer, and we can say that there are likely to be big 
differences in the incidence of high risk genes in the 
Marsden population versus the NSABP population.  It is a 
factor of 2 or 3.  It is likely to be that different. 
	DR. DUTCHER:  Dr. Ozols?
	DR. OZOLS:  I am concerned about what additional 
information we are going to get in the future.  We know what 
the NSABP follow-up trial is.  You alluded to some trials 
that are going to be done in Europe.  Do you have data on 
some of those plans?
	DR. POWLES:  Well, the Italian trial has 5000 
women in it, and it is a different population from the pilot 
trial, our trial, which has 2500 women in it.  The national 
British trial has 4500 women at the moment.  So, between the 
3 of them -- I can't add that up in my head but there is 
11,000 or 12,000. 
	One of the concerns we obviously have about this 
hearing is that we would like to be able to hold those 
trials together, having those numbers of women.  We are 
still accruing to the British national trial which we would 
like to take up to a total of 10,000 women.  If we can hold 
those trials together through incidence data, we hope that 
we will be able to get identification of clinical benefit in 
those trials. 
	DR. DUTCHER:  Other questions?  Dr. Simon?
	DR. SIMON:  Dr. Powles, what percentage of your 
invasive breast cancer cases were ER positive? 
	DR. POWLES:  We haven't completed that yet.  We 
are doing it at the moment but we haven't completed that. 
Open Public Hearing
	DR. DUTCHER:  Thank you very much.  We have half 
an hour allotted now for an open public hearing.  We have 
six people who have requested to speak.  We ask that they 
each state their name, identify themselves and their 
sponsors for participation, and then following the open 
public hearing we will proceed with the committee discussion 
and vote.  The first person is Ann Fonfa.  We would ask you 
to use the podium if possible.
	MS. FONFA:  My name is Ann Fonfa.  I am a five and 
a half year breast cancer survivor.  I consider myself an 
activist.  I am very glad to be here today because I have a 
very strong point of view on what we have heard, and much 
stronger on what we haven't heard.
[Voice on telephone:  "Thank you for saving me 
from breast cancer.  Today, I had a pulmonary 
embolism.]
	Survival is what counts for cancer patients.  What 
I heard here today only aggravated the feelings that I felt 
when I first read the newspaper information and everything 
that has been published so far about the trial. 
	Women died of breast cancer who took placebo; 
women died of breast cancer who took tamoxifen; women died 
of pulmonary embolism who took tamoxifen.  This pains me 
because as far as I can see when you are dead, you are dead.  
It doesn't matter what you died from.  I have a great 
concern about women who come in healthy and die because of 
something that they take, thinking that it is going to 
prevent them from dying from something else.  There is a 
real problem here.
	Some of my concerns include the fact that for 
tamoxifen, while we hear that there are hundreds of 
thousands of hours of follow-up, it is actually not very 
lengthy in time.  And, time I think is what will indicate 
what may be further problems when healthy women are given 
this drug. 
	So, all we have is really a 5-year or less 
follow-up, and from what I heard today, the follow-up is 
really very shaky.  It is if the women consent, if the 
company consents, and if we are able to continue to look at 
what happens.  We don't know whether women who are healthy 
take tamoxifen at this point and whether they benefit for 
any length of time afterwards.  Yes, we can say that there 
haven't been any cases but how far out are we from the end 
of the study?  We are not even 6 months.  So, we are not 
looking at any long-term follow-up right now to say, yes, 
there has been a tremendous benefit conveyed; that these 
women now are safe from breast cancer for the future.  We 
don't know at all that they are. 
	So, my point is really that there are endless 
questions about what is going on, and I think it is way too 
soon to allow this drug to be in the general population 
because you know darned well that once doctors are able to 
prescribe it -- you know, let's face it, we have had very 
good success in making people aware that there is an 
epidemic of breast cancer and, therefore, lots of women are 
going to want it from doctors and lots of doctors are going 
to give it to the women regardless of their risk-benefit. 
	Women with cancer and women without cancer are not 
foolish.  They need information.  We have presented the 
trial as being prevention when it has clearly been indicated 
today that it is not; it is really a risk reduction and that 
should be made very, very clear to the population and to the 
physicians.  I think that is very important. 
	And, once it is out in the trenches, which is what 
I call the world of women who have cancer and the women who 
fear cancer, they are not going to be able to hold to the 
standards that are established, and you have to be aware of 
that in a very serious way.  Women will be asking for it; 
doctors will be granting it.  We know they are doing that 
now with lots of other drugs. 
	I envision a situation in which you go to see your 
doctor and the doctor says, "do you want hormone replacement 
or do you want tamoxifen?" and, you know, you are on a pill 
taking care of something that may or may not be useful.  We 
don't know yet.  My main point has been questions.
	I came here waiting to hear what was presented, 
figuring I would start my talk based on everything I heard, 
but I didn't hear anything that actually changed my point of 
view.  There has been no new information.  There are still 
tons of questions. 
	We are saying women under 49.  Women under 49 is a 
huge category.  A young woman in my organization, in New 
York, has been talking to be about the idea that women under 
35 may have different standards.  We haven't heard a word 
about that subset and that is really scary to me.  Yet, 
women under 35 who have high risk, who have family 
connections, who are fearful of breast cancer -- how are 
they going to know what to do?  We don't have any 
information.  Women of color -- we have no information.  We 
are leaving out all these subsets of populations, saying, 
well, women over 60, we will just give them tamoxifen if 
they are not taking hormone replacement, or maybe they will 
be taking both.  There is something wrong with this picture.
	I have a very, very strong concern about where 
this is going to go.  Remember that when doctors are 
prescribing it, when you are out in your doctor's office 
asking what you should do and talking about your risks and 
benefits, there are a lot of blurred lines.  It is not going 
to be clear.  However many scientists here are truly clear 
about what they have heard and what they have found out, it 
is not going to be clear in the doctor's office.  It is 
going to make a difference.  Women will not know what to do.  
I think we need a lot more information.
	I have a concern about the fact that we are saying 
we only need one trial here, in the United States.  That is 
a concern for me.  I don't feel that is a benefit for 
patients or for healthy women or high risk women.  I think 
we are rushing things in a way which we should not be doing.  
There is no reason to.  It is not even like that many women 
got breast cancer within the trial.  If they are really high 
risk -- I just don't see this.  It is not strong enough for 
me. 
	Also, we saw a slide that said the tamoxifen study 
began in 1978.  So, overall we don't even have long-term 
follow-up to know what is going on.  Leslie Ford was quoted 
in the Journal of NCI, Volume 88, August 28, 1996:  
Tamoxifen has been available for 30 years.  It wasn't until 
the late 1980s that we found about tamoxifen in the uterus.  
Again, I say that over time they find things out that we 
don't find in the hours of use because that is not the same 
thing.  You can have 300 women take it for an hour each and 
that is 300 hours but it is not the same as having long-term 
years out and we need to see those effects. 
	So, my main point really is that we don't know 
enough to go forward on this at this time, and I really feel 
we need more studies; we need more information.  That is 
really about all I have to say.  Does anyone have any 
questions for me?  I would also like to point out that no 
drug company has ever paid me for my opinions.
	[Laughter]
	DR. DUTCHER:  Thank you.  The next speaker is 
Cindy Pearson.
	MS. PEARSON:  Good morning.  I am Cynthia Pearson.  
I am the Executive Director of the National Women's Health 
Network.  The Network is supported by a national membership 
of individual and local organizations, and we do not accept 
money from pharmaceutical companies or manufacturers of 
medical devices.  The Network urges the FDA and the 
committee that has been asked by the FDA to give it advice 
not to approve tamoxifen for prevention or even for risk 
reduction at this time.
	Now, how can we take such a strong negative stand 
when women in the United States and the world have been 
hearing such positive comments about tamoxifen and the 
results in the breast cancer prevention trial since April 6?  
Federal officials, including the Director of the National 
Cancer Institute, Richard Klausner, and Donna Shalala, 
Secretary of Health and Human Services have called the trial 
and its results and the drug tamoxifen stunning, remarkable 
and a historic success? 
	Well, our questions about the trial and the drug, 
and whether this is the right time for approval for its use 
in risk reduction -- some of them have already been brought 
up by Dr. Powles, by Ann and others, but we would like to go 
over them again so that you and the FDA are aware of the 
concerns from all the places that are coming to the FDA.
	We share the concern that has already been 
expressed about whether or not prophylactic tamoxifen will 
save lives.  As you saw in the data earlier this morning, as 
of right now it is not possible to say that a single woman's 
life has been saved by taking tamoxifen for prevention, as 
far as we can tell from the breast cancer prevention trial, 
and it seems more and more obvious that the breast cancer 
prevention trial will never actually be able to tell us 
anything about whether or not tamoxifen can save women's 
lives, tamoxifen taken for prevention. 
	Dr. Klausner says he only has guaranteed 2 years 
of funding for follow-up.  As you heard earlier, many of the 
women who were originally on placebo are now taking 
tamoxifen.  But what you haven't heard very clearly is that 
since April the NCI has publicly announced, and has taken 
steps to effectuate the active recruitment of placebo women 
to the STAR trial which has no placebo group.  So, if the 
NCI's efforts are successful there will be little control 
group left to follow-up even if there were a guarantee of 
more than 2 years follow-up.  I see someone nodding, 
whispering, "that's true, actually."
	So, why are we stressing so much our concern that 
we do not yet know if tamoxifen for prevention saves lives 
and are likely not to ever know it from the BCPT?  It is 
because the early data are troubling.  We heard over and 
over again from the sponsor and the NSABP people this 
morning that the data at 4 and 5 years show no harmful 
trends; that there isn't an increase of the ER-negative 
cancers; that none of the effects that started to be seen at 
1 and 2 years changed for the worse at 4 and 5 so that the 
long-term effect should be as good as the short-term 
effects. 
	But that is not true with treatment, and everyone 
at this table knows it.  It took eight and a half years of 
long-term treatment with tamoxifen in breast cancer for 
survivors to see that going beyond 5 years actually caused 
more recurrences and more deaths from breast cancer than 
stopping tamoxifen treatment at 5 years.  So, we absolutely 
need to know those long-term data, which we are going to 
have trouble getting.  As you cleverly questioned the 
sponsor this morning, we don't even really know all the 
prognostic data on the women who have been diagnosed in this 
very short period of time. 
	So, to play out the worst case scenario, we 
already know that estrogen-receptor negative cancers are not 
even delayed by tamoxifen for prevention.  We don't yet know 
whether estrogen-receptor positive cancers are delayed, 
prevented or merely delayed, which would mean we would have 
no net effect on numbers of cancers.  And if, even worse, 
this early pretreatment of non-detectable breast cancers 
with tamoxifen results in the same sorts of resistance and 
aggressiveness that we see with long-term treatment of 
detected and diagnosed breast cancer, we could have the same 
number of cancers in women who have taken tamoxifen for 
prevention but with a worse prognosis and even a harmful 
effect on mortality.  So, this is why we have emphasized it 
so much, and believe that we just don't know enough now to 
change the label and tell the women of America that 
tamoxifen can be used to prevent breast cancer.
	Our other concern is if tamoxifen were to be 
described to women and doctors in the United States as a 
approved for prevention breast cancer, will more women be 
hurt than helped?  That question is answered primarily by 
how many women will take tamoxifen and who will they be and 
what will their level of risk be. 
	We know that even in the ideal environment of a 
tightly controlled research time not all risks can be 
prevented.  We know that if any of you were asked, as I am 
sure you already have been, for tamoxifen by a woman who 
hasn't yet been diagnosed with breast cancer, you would give 
a very reasoned analysis.  Some of you would go even further 
than the Gail model and look to who actually was in this 
trial -- as we saw, women who had double the risk that the 
Gail model requires.  But do you really think that every 
primary care doctor and gynecologist in America could give 
that kind risk?  Do you think that the lovely little, nicely 
designed risk model information, user-friendly description 
of the Gail model that Leslie Ford held up in her hands is 
enough?  I don't think so.  I think that as other speakers 
have said, busy doctors are going to respond to women's 
expressed needs.  As you know, women already have quite a 
high concern about the likelihood of being diagnosed with 
breast cancer.  If we add FDA approval to this, we are 
giving the manufacturer a green light to start direct to 
consumer advertising. 
	So, if you add the concern that is already there, 
and the limited time that most physicians have to have these 
conversations, if you add in a high powered marketing 
campaign, we are in for potentially 29 million users of 
tamoxifen. 
	I am getting the signal that I need to close up.  
We, again, conclude with saying we urge you to recommend 
against the approval for tamoxifen for risk reduction at 
this time. 
	We have appended to our remarks suggested labeling 
language about how to better educate physicians and women as 
to who might or might not benefit in the short-term from 
tamoxifen, and maybe later there will be time to go over 
that. 
	Thank you for the opportunity to testify, and I 
wonder if there are any questions for me. 
	DR. DUTCHER:  Dr. Simon?
	DR. SIMON:  Could you summarize briefly, based on 
the uncertainties of long-term benefit and the risks, is 
there a group of women who your organization believes the 
risk-benefit ratio might be favorable for?
	MS. PEARSON:  I think our organization agrees with 
almost everyone who has addressed that so far today, that 
women who already have been diagnosed with lobular carcinoma 
in situ, if -- and it is an important "if" -- if they are 
fully informed about the risks and benefits, the fact that 
the positive effects right now are based on one trial that 
is yet to be confirmed, and the complications associated 
with it -- if there is good information sharing, that is a 
group of women for whom even this limited short-term 
knowledge would be enough; useful.
	DR. SIMON:  Is that the only group?
	MS. PEARSON:  That is the easiest group to answer 
it.  In our language, which I know I don't have time to 
read, we suggest that every woman considering this go 
through a formal risk assessment.  Then we recapitulate the 
findings of the BCPT based on who actually took part in it, 
not based on what the entry criteria were, which was that 
for women over age 50 with a uterus there was no net health 
benefit.  Breast cancer cases were delayed or prevented in 
the time of the trial but as many, and even slightly more at 
least as of January 31st, as many other life-threatening 
events took place. 
	For women over age 50 with a hysterectomy, there 
appears to be, based on the short-term data, a net health 
benefit if the risk of breast cancer is 2-3 times that of 
the general population of women that age.  For women under 
age 50, it takes 5 times risk compared to the general 
population of women that age to get a net health benefit. 
	DR. DUTCHER:  I might say that in the handout from 
her organization there is a copy of those indications you 
can look at.
	MS. PEARSON:  Are there any other questions? 
	DR. DUTCHER:  Dr. Raghavan?
	DR. RAGHAVAN:  Just for clarification, one of the 
things that I have heard you and Miss Fonfa talk about is 
the risk to the people taking tamoxifen in terms of what 
might happen and deaths unrelated to breast cancer, and so 
on.  Yet, the NSABP figures show that 65 people dies on the 
placebo arm and 53 on the tamoxifen arm.  I understand the 
numbers are small but any way you cut, slice or dice it, it 
still means more deaths in the placebo arm.  Does that not 
affect how you view this in some way?
	MS. PEARSON:  No, it doesn't.  That effect is not 
statistically significant, and it is based on short-term 
data where we have these troubling hints from the long-term 
treatment that the use of long-term tamoxifen in breast 
cancer survivors might indicate that its effect on breast 
cancer will start to worsen. 
	DR. DUTCHER:  The next speaker is Vincent Li. 
	DR. LI:  My name is Dr. Vincent Li.  I am the 
Scientific Director of the Angiogenesis Foundation, and 
neither I nor the Foundation have any financial interests in 
Zeneca.
	Breast cancer afflicts 1.8 million women in the 
U.S. and it is a highly angiogenic tumor.  By this, I mean 
that breast tumors must initiate angiogenesis, new blood 
vessel growth, in order to grow beyond 1-2 mm in size.  This 
brings oxygen, nutrients and growth factors to the tumor.  
New blood vessels also provide an escape route for breast 
cancer cells to metastasize to other sites in the body.  The 
smallest palpable breast cancer is 1 cubic centimeter and 
already contains 1 billion cancer cells.  To supply the 
metabolic demands of those cancer cells, between 10 to 100 
million blood vessel cells will have already invaded the 
tumor.  Therefore, anti-angiogenic drugs are being developed 
to cut off the blood supply from established tumors. 
	This approach is currently in clinical trial for 
some 26 experimental agents around the world but the 
treatment of large, established cancers is only one goal.   
The Angiogenesis Foundation believe that an equally 
important goal is to develop chemopreventive strategies that 
can prevent even the smallest tumors from gaining the 
ability to create a new blood supply. 
	We believe that Nolvadex is the first 
chemopreventive drug that may benefit patients at risk for 
breast cancer through anti-angiogenesis.  Tamoxifen is an 
angiogenesis inhibitor, as well as an anti-estrogen drug.  
In tissue culture it inhibits vascular endothelial cell 
growth.  It inhibits angiogenesis ex vivo in the chick 
chorioallantoic membrane assay.  In mice implanted with MCF7 
human breast cancer cells tamoxifen inhibits tumor 
angiogenesis as well as tumor growth.  When given long-term 
in animals, tamoxifen suppresses malignancies, and this 
preventative effect has been attributed to angiogenesis 
inhibition as well. 
	The Angiogenesis Foundation is a non-profit 
organization dedicated to bringing new angiogenesis 
therapies to the world through education, research and 
innovation.  Each week we receive hundreds of telephone 
calls from patients, including many breast cancer patients, 
seeking information on angiogenesis therapies.  Patients in 
remission, as well as women at high risk for breast cancer 
ask us about chemoprevention. 
	In 1994, the Foundation identified tamoxifen 
citrate as a potential anti-angiogenic chemopreventative 
agent.  In that same year, researchers from the National 
Cancer Institute published a paper in the Journal of 
Cellular Biochemistry supporting our idea.  Based on our 
analysis of the breast cancer prevention trial, we offer the 
following insights for ODAC's consideration:
	First, there is a sound biological rationale for 
tamoxifen's use in chemoprevention based upon its 
anti-angiogenic as well as its anti-estrogen properties. 
	Second, tamoxifen is still relatively devoid of 
harmful effects compared to the consequences of breast 
cancer. 
	Third, tamoxifen's approval for this indication 
will stimulate the pharmaceutical industry to develop 
further generations of chemopreventative drugs, including 
other anti-angiogenesis agents. 
	Fourth, tamoxifen's approval may uncover 
additional beneficial anti-angiogenesis effects when they 
are looked for specifically, for example suppression of 
diabetic retinopathy, psoriasis, arthritis, or the 
suppression of other non-breast cancers.
	A few words of caution are warranted, however.  
Tamoxifen's use for chemoprevention may lead to primary care 
doctors or nurse practitioners to prescribe the drug to 
women who do not fall into high risk categories, and this 
has been spoken about by others, due to pressures from their 
patients or from a perceived benefit.  Our concern is that 
some women taking chemoprevention may avoid the gold 
standards of self-examination, routine physician visits and 
screening mammography. 
	Long-term use of tamoxifen may also lead to some 
undesirable side effects of anti-angiogenesis, for example, 
inhibition of coronary angiogenesis, delayed wound healing 
after surgery and fetal malformation.  The Angiogenesis 
Foundation is studying this problem because it will be 
necessary to achieve the desired effect of anti-angiogenesis 
without disrupting the body's ability to generate beneficial 
blood vessels.
	Finally, tamoxifen is associated with a slight 
increase in the incidence of endometrial cancers, and there 
is an angiogenesis base of mechanism for this as well.  
Animal studies have shown that tamoxifen can up-regulate 
mRNA expression of the angiogenic factor VEGF, vascular 
endothelial growth factor, in uterine tissues, and this may 
be a concern for women at high risk for endometrial cancer.
	In summary, tamoxifen is an estrogen blocker with 
anti-angiogenic properties.  Its therapeutic effects are 
likely due in part to inhibition of breast cancer 
angiogenesis.  If Nolvadex is approved for breast cancer 
chemoprevention, we emphasize the need to educate women on 
the continued importance of self-examination, regular 
checkups and screening mammography.  Prescribing doctors 
must watch for possible harmful effects, as well as any 
additional beneficial effects, of long-term 
anti-angiogenesis in women.
	Thank you very much. 
	DR. DUTCHER:  Thank you.  Our next speaker is 
Helen Schiff. 
	MS. SCHIFF:  My name is Helen Schiff.  I am a 
breast cancer activist and survivor. 
	When you look at the results of the breast cancer 
prevention trial, the reduction of breast cancer incidence 
of 45 percent is stunning.  I remember thinking when I first 
read the newspaper that there probably is a group of 
ultra-high risk women for whom the benefits would outweigh 
the risks.  I was happy some women might be helped.  But the 
more I studied the results of the trial, the more I read the 
pros and cons, the more I thought about it, the more I began 
to worry -- worry about giving tamoxifen to a healthy 
population.
	I would like to share my worries with the advisory 
committee and with the FDA, and hope that they worry about 
them too.  I worry that the prevention trial was designed to 
look only at breast cancer incidence.  Shouldn't incidence 
of other life-threatening diseases caused by tamoxifen, such 
as uterine cancer and deep vein thrombosis and pulmonary 
embolism be weighed too?  Further, isn't death really the 
most important endpoint? 
	I worry that even though there is less breast 
cancer incidence in the tamoxifen arm, will there be less 
breast cancer mortality?  I am not the only one who worries 
about this.  Dr. Ken Osborne, a leading breast cancer 
researcher and clinician was quoted in the June issue of 
Oncology Times as saying, and I quote, tumors that develop 
on tamoxifen have a somewhat poorer prognosis than those 
that develop on placebo, suggesting that there is a 
treatment effect on an established tumor.  Over time, 
mortality between the 2 groups may not be that different. 
	I worry that the trial was too short to know if we 
are preventing breast cancer or holding it in check for only 
a short time, after which a tamoxifen-resistant tumor 
develops that does not respond to hormonal treatment.  
Again, it is not just me.  Dr. Osborne says, and I quote, a 
major question is whether these drugs affect only 
preclinical breast cancer or are true prevention agents.  We 
don't know if these drugs block cancer at earlier stages.  
We may learn from the longer European studies. 
	I worry that the trial is too short for all side 
effects to emerge.  Is that why premenopausal women on the 
tamoxifen arm showed no bone loss, contrary to the results 
of all previous trials? 
	I worry that the average length of time on the 
treatment arm is shorter than the overall 4-year average 
because over 30 percent of the drop-out rate could have been 
unequally distributed between each arm, and we just heard 
today that it was. 
	I worry that the reason we don't know what the 
distribution of the drop-out rate was is because the trial 
has not been published in a peer reviewed journal, as the 
Italians and British trials were.  I worry about what else 
we don't know because the trial was not published in a peer 
reviewed journal.  As was brought up toady by one of the 
panel members, we don't know at how high a risk the actual 
participants in the trial were.
	I worry that we don't know if tamoxifen works for 
women with BRCA 1 and 2 mutations, the very population most 
likely to want it. 
	I worry about the long-range effects on tamoxifen 
blocking estrogen receptors in the brain, causing memory 
loss and other cognitive deficits. 
	I worry that using the breast cancer treatment 
trials to validate prevention trials is like comparing 
apples and oranges.  They are two different populations. 
	I worry because I learned in Project Lead, the 
National Breast Cancer Coalition program for breast cancer 
advocates, that you need more than one trial to validate 
results, and we don't have that.  In fact, we have two 
trials that don't validate the results.
	I worry that if the drug is approved women's 
exaggerated fear of breast cancer, couples with advertising 
publicity, will cause irreparable harm.  This drug will 
mainly be prescribed by primary care physicians and 
gynecologists, not oncologists. 
	I worry about approving a drug with 
life-threatening side effects for a disease that a large 
majority of the indicated population won't get, and those 
who do won't die from it.  Breast cancer is not an automatic 
death sentence.  The relative survival rate is 50-60 percent 
out to 15 years.  We need more data and longer trials to 
make an accurate risk-benefit analysis.  We want prevention 
for our daughters, sisters and mothers and for all women.  
We want answers but we are willing to wait for them to make 
sure they are right. 
	I just have one question to ask, if there was any 
breakdown done on premenopausal women younger than 40, the 
35-40 age group or for the 45 age group down. 
	DR. DUTCHER:  Thank you.  The next speaker is Mary 
Ann Napoli.
	MS. NAPOLI:  I am Mary Ann Napoli, from the Center 
for Medical Consumers in New York.  We are a public interest 
advocacy organization.  In the 21 years we have been in 
existence, we have never sought nor accepted pharmaceutical 
industry money. 
	The Center for Medical Consumers strongly urges 
the committee not to approve for the new indication.  My 
organization has long been concerned about the growing trend 
in this country towards treating a risk factor as if it were 
a disease.  Direct to consumer advertising of prescription 
drugs to prevent bone loss, to lower cholesterol and so 
forth reinforces the idea that common manifestations of old 
age must be treated at menopause, and that people, 
particularly women, couldn't possibly live a long, healthy 
life without the aid of protracted drug therapy. 
	As an example of distorted ads to the public, I 
have brought one along from Good Housekeeping magazine.  
Though Bristol-Myers Squibb is selling cholesterol-lowering 
drugs to women without heart disease in this ad, it stands 
as an example of what is ahead for us if tamoxifen is 
approved as a preventor.  The woman in this ad -- you are 
going to have to take my word for it because you are all so 
far away, but the woman in this ad looks to be about 40.  
The lone study to support this ad claim did, in fact, have 
female participants but their average median age was 63.  
Women entering middle age, rather than elderly women, are a 
favorite target audience of drug companies, and that is for 
good reason -- they tend to be more receptive and they have 
a longer life span ahead in which to take drugs. 
	To show that misleading ads to the public are not 
confined to the consumer, I have brought Merck's ad to 
doctors for fosamax.  This ad appeared repeatedly in Annals 
of Internal Medicine in 1996.  Next to the woman's face it 
encourages doctors to prescribe no matter what her degree of 
bone loss.  Here too you are going to have to take my word 
for it.  She looks like she is no more than 50.  At the time 
of this ad campaign, the only evidence to support the drug's 
ability to prevent bone loss was entirely confined to 
elderly women. 
	We don't know whether Zeneca is going to be a 
irresponsible in its advertising, but we already know that 
there is a precedent for allowing it to happen.  You add to 
this precedent the fact that this is a country in which 
breast cancer awareness activities have caused younger women 
in particular to vastly overestimate their odds of getting 
breast cancer.  Middle aged women are very familiar with 
that laundry list of risk factors for breast cancer that 
frequently appears in the lay media, and that laundry list 
tends to emphasize the woman's reproductive history.  In 
fact, I can't think of a single list that told women how 
important being over 60 is. 
	Misleading ads and overestimation of risk makes 
for a worrisome combination.  Any drug billed as a 
preventive to the public is likely to be taken literally.  
Even if physicians confine their prescribing of tamoxifen to 
women who are truly at high risk, keep in mind that most of 
these women will not die of breast cancer.  More likely, 
they are going to die of heart disease.  Scientific data, by 
definition, can be replicated.  Obviously, the U.S. 
tamoxifen trial's most significant benefit has not been 
replicated, nor has it been published in a peer reviewed 
journal.  For these two reasons alone, the advisory panel 
should not approve it for the new indication. 
	While the equal number of deaths in the tamoxifen 
and the placebo groups may not be statistically significant, 
it is certainly a red flag that indicates caution in 
approving tamoxifen on the basis of the trial that only 
lasted four and a half years.  When long-term drug therapy 
is contemplated for healthy people, it becomes imperative 
for the panel to be even tougher on the supporting evidence 
than you would be if you were assessing evidence to support 
a drug given to people with an established illness. 
	Here is a drug known to increase the risk of 
cancer and potentially fatal blood clots.  Prescribing 
physicians who want to help a woman who is fearful of 
developing breast cancer would want to be sure that they are 
not causing her more health problems.  They would want the 
panel's assurance that the consequence of their prescribing 
would be more than simply changing what it says on her death 
certificate.
	Thank you.
	DR. DUTCHER:  Thank you.  The next speaker is 
Sharon Batt.
	MS. BATT:  Madam Chairman, members of the 
committee, thank you for the opportunity to testify today.  
My name is Sharon Batt, and I am a breast cancer survivor.  
I am here on behalf of Breast Cancer Action, Montreal, a 
public interest organization representing women with breast 
cancer, their families and friends. 
	About 700 Montreal women took part in the breast 
cancer prevention trial.  While the outcome of this hearing 
will not directly set policy in Canada, the FDA's decision 
will affect Canadian public opinion and will influence 
regulators in Canada and elsewhere. 
	We ask the FDA not to approve the application for 
the preventive use of tamoxifen.  The 600 million dollar 
question addressed in this trial was whether tamoxifen can 
prevent breast cancer.  Despite the statistically 
significant difference in breast cancers between the 2 
groups, the trial did not answer the question that was its 
raison d'etre, and other people have discussed that and made 
that point very well so I won't belabor it.
	Even if tamoxifen prevents breast cancer, the 
rationale for approving the drug is tenuous because the 
risks are considerable.  We simply don't have enough 
information to effectively steer women from serious harm.  
Even with the careful efforts to screen women at risk for 
life-threatening events, deaths occurred.  Outside the 
protected confines of a trial, they will surely occur more 
often. 
	Several people have mentioned the BRCA gene, and 
the fact that this population is probably the one that is 
most motivated, will be the most motivated to take tamoxifen 
for prevention.  Yet, we don't know if women carrying a 
mutated BRCA gene are more likely to benefit from tamoxifen 
or less.  The British study suggests that these women may 
not benefit at all. 
	It is commendable that the NSABP is planning to 
proceed with testing for this factor but surely drug 
approval should await results of the BRCA testing so that 
the women from this key high risk group can make an informed 
decision about prophylactic tamoxifen use. 
	I haven't heard any comments about the issue of 
pregnancy.  We have no data on pregnancy and tamoxifen to my 
knowledge.  This drug has only been used by women who have 
breast cancer or women in a clinical trial.  If the drug is 
approved for widespread preventive use, surely some women on 
tamoxifen will become pregnant and carry those pregnancies 
to term.  Although data on risks to a human exposure of 
tamoxifen in utero is lacking, animal experiments show 
deformities. 
	Everything about this trial has progressed "pedal 
to the metal."  The urgent need of women has been 
incessantly invoked, first to launch the trial, then to stop 
it, then to go public, and now to take the drug to general 
use.  Surely, it is time to pause, take our collective 
breath and reflect on what course would truly benefit women.
	In 1992, the FDA ruled on another controversial 
product concerning women.  Dr. David Kessler announced that 
silicone implants would be available only through controlled 
clinical trials until questions about their efficacy and 
safety were answered.  I ask this committee to recall the 
principles behind that decision. 
	The first was that manufacturers, by law, must 
prove their products to be both efficacy and safe before 
they may be distributed and used. 
	The second was that the FDA has a duty to mediate 
between the vested interests of manufacturers and the 
interests of patients.  The rationale for FDA intervention 
is greatest precisely in cases where vulnerable members of 
the public are hoping against hope for a medical solution to 
a deeply felt need. 
	Finally, Dr. Kessler argued that meaningful data 
was needed to answer the outstanding question about safety 
and efficacy of breast implants.  The only way to assure 
that this information would be collected was for the FDA to 
restrict the product's availability to clinical trials. 
	I urge this committee to uphold the standard of 
this previous ruling and to protect the public interest.  
The interest of science and sound medical practice will 
benefit as well. 
	Thank you.
Committee Discussion and Vote
	DR. DUTCHER:  Thank you, and I want to thank all 
of the public for coming and expressing their views and 
demonstrating a high level of involvement.  I think many on 
the committee have expressed some of the same questions and 
concerns, and I think we have to decide whether we feel we 
can safely generate guidelines, or where we stand with this.  
So, we are going to have to go ahead with discussion. 
	The first page of the questions to the committee 
describes the trial -- prospective, multicenter, randomized, 
double-blind, placebo-controlled trial of tamoxifen versus 
placebo for 5 years in women at increased risk for breast 
cancer as determined by age, prior history of lobular 
carcinoma in situ, or 1.7 percent risk of developing breast 
cancer in the next 5 years as predicted by the Gail model.  
And, 13,388 women were randomized, 6707 on placebo and 6681 
on tamoxifen.  The objectives of the trial were to test the 
ability of tamoxifen to prevent invasive breast cancer, 
mortality from cardiovascular disease, and bone fractures, 
and to assess the toxicity and safety and effects of 
tamoxifen in this patient population.
	The results of the trial, per FDA review, are 
summarized in the following table.  Events have been 
categorized by age at diagnosis of the event rather than age 
at randomization.  So, I will give you a moment to look at 
the table. 
	The first question, is the NSABP P-1 an adequate 
and well-controlled trial demonstrating the efficacy of 
tamoxifen for the prevention of breast cancer in women at 
increased risk as defined by the study?  Dr. Sledge, do you 
want to discuss it?
	DR. SLEDGE:  Well, I guess I would have to say I 
agree with most of the statement but not all of it.  The 
concern that I think both Dr. Albain and I raised is with 
use of the word "prevention."  This is a trial of very short 
follow-up.  Everything we know about breast cancer is that 
it is a disease that takes a long term to go from a 
premalignant to an invasive, malignant state.  Here, we are 
seeing effects within a year of starting the drug.  While 
those may be beneficial effects in and of themselves, they 
are not prevention in the way that scientists understand the 
word prevention. 
	So, I would have to say that while I would be 
comfortable saying that we have demonstrated risk reduction 
with this very well-controlled, very well-performed trial, I 
don't think it has met the bar of what a scientist would 
consider a chemopreventive effect. 
	DR. DUTCHER:  Dr. Albain?
	DR. ALBAIN:  Those were almost exactly my words 
too.  It is clearly a well-controlled trial, and there has 
been a very significant reduction in events at this time.  
Regardless of what we think about the biology in patients 
who have already had one cancer versus this population, it 
is remarkable how much it agrees with the reduction of 
contralateral breast cancer in patients with one cancer. 
	I think our concerns is with this word 
"prevention."  I don't think we are seeing that yet.  I hope 
that we will see it as this trial is followed but we haven't 
had the time to say that we can use that word.  In 
particular, as was just pointed out earlier in the 
discussion, after the study drug is stopped there is a 
higher rate of cancers reported in the tamoxifen group than 
the placebo, at least by the percentages that were shown by 
the FDA review, 46 percent, 39/85, occurred after the study 
drug was stopped versus 34/154, 22 percent, in the placebo 
arm.  But there is a very encouraging cumulative curve that 
we saw that as this trial is being followed the curves are 
not coming together; they are staying apart and that is what 
we would expect from contralateral breast cancer data as 
well.  So, again, we need some more time to be certain that 
we are seeing prevention.
	DR. DUTCHER:  Dr. Simon?
	DR. SIMON:  I guess I have one additional concern 
with it as it is written -- prevention of breast cancer in 
women at increased risk as defined by the study.  I think 
the study demonstrated either something like risk reduction 
or delay of diagnosis in a group of women at increased risk.  
One of my big problems is I am not very sure as to what that 
group is but I don't think it has demonstrated it in women 
in general at increased risk, or even using the risk as 
defined in the protocol.  I think there is a group of women 
who are at increased risk who had fewer invasive breast 
cancer events over this time period, but I think there is a 
problem with categorizing who they are. 
	DR. DUTCHER:  Dr. Justice?
	DR. JUSTICE:  I think your points about the 
terminology are well taken, and we would be happy if the 
committee would like to rephrase the question and subsequent 
questions to use terminology that is more appropriate, such 
as was mentioned -- reducing the risk for the duration of 
the trial.
	DR. DUTCHER:  So, let me give it a try and see 
what you think.  Is NSABP P-1 and adequate and 
well-controlled trial demonstrating the efficacy of 
tamoxifen for risk reduction of breast cancer in a group of 
women at increased risk for the duration of the trial, or do 
you want a duration on this?  Dr. Margolin?
	DR. MARGOLIN:  I think it was the issue of how to 
define the population, and something to the effect of rather 
than as defined by the study entry criteria, it was as 
defined by those who were studied, or, you know, something 
of that nature -- women who are like the ones who were 
studied. 
	DR. JUSTICE:  Let me try it again.  How about 
saying for the reduction in the risk of breast cancer in 
women who were studied on the trial? 
	DR. DUTCHER:  Good. 
	DR. JUSTICE:  Or women with characteristics.
	MS. BEAMAN:  And, exactly how would that transfer 
to "Woman Q. Public?"
	DR. DUTCHER:  That is down the road here I think.  
That is to be defined, you are absolutely right.
	Is NSABP P-1 an adequate and well-controlled trial 
demonstrating the efficacy of tamoxifen for reduction of 
breast cancer in a group of women comparable to those 
studied in the trial? 
	DR. ALBAIN:  Reduction of risk of breast cancer? 
	DR. DUTCHER:  Risk reduction.
	DR. SCHILSKY:  How about reducing the risk of 
developing?
	DR. DUTCHER:  Demonstrating efficacy of tamoxifen 
in reducing the risk of breast cancer?
	DR. ALBAIN:  We can also say reducing the 
incidence of breast cancer. 
	DR. DUTCHER:  Risk?  Incidence?  Risk?  Is risk 
okay?  The risk in a group of women comparable -- well, in 
the women studied in the trial.  That is what it was really 
demonstrating. 
	DR. SIMON:  I mean, the most accurate thing would 
be reducing the short-term incidence of breast cancer. 
	DR. RAGHAVAN:  We should put a time frame on it. 
	DR. DUTCHER:  Okay, reducing the risk of breast 
cancer, the short-term incidence.  Okay, demonstrating the 
efficacy of tamoxifen in reducing the short-term incidence 
of breast cancer in the women entered in the trial. 
	DR. ALBAIN:  In women comparable to those entered 
in the trial? 
	DR. DUTCHER:  Well, I mean, we will have to make a 
recommendation of the patient population, but basically the 
trial demonstrated in the patients that were in the trial.  
Carolyn, you are not happy?
	MS. BEAMAN:  I guess I am not really clear on who 
they were.  Who were they? 
	DR. DUTCHER:  Well, I think what we are trying to 
say is that in the patients as entered in the trial, and 
when Dr. Honig presented her analysis of the subgroups it 
seemed that every subgroup demonstrated a reduction.  We 
will have to decide the risk-benefit ratio, which we are not 
talking about in this one.  Do you want to look at the 
tables again? 
	DR. SIMON:  I mean, I guess I don't believe that 
every subgroup demonstrated a reduction just because they 
were looked at one at a time.  But I think if we word it 
this way we are not really saying it is for every subgroup.  
We are just saying there was a group of women who were 
studied on this trial -- we are going to have to grapple in 
the following questions with who they were and who the 
risk-benefit is appropriate for.  Basically the women who 
were on this trial, within this time frame they had a 
reduction in the incidence of breast cancer.
	DR. DUTCHER:  So, let me read it again omitting a 
few more words.  Is NSABP P-1 an adequate and 
well-controlled trial demonstrating the efficacy of 
tamoxifen in reducing the short-term incidence of breast 
cancer in women entered in this trial, which could be all or 
some.  Is that acceptable language? 
	All those who would vote yes?
	[Show of hands]
	Eleven yes. 
	All those who don't know?
	[No response]
	Zero. 
	The next table is to discuss adverse events.  I 
will give you a moment to look at that.  The mortality, 
breast cancer-related mortality, and occurrence of other 
cancers were not significantly different between the two 
arms.  The table points out invasive endometrial cancer, 
DVT, pulmonary emboli, stroke, cataract surgery, hot 
flashes, discharge. 
	Does NSABP P-1 demonstrate that tamoxifen has a 
favorable benefit-risk ratio for the short-term reduction of 
breast cancer in women -- well, I will read it as it is and 
then we can change it -- a favorable benefit-risk ratio for 
the prevention of breast cancer in women at increased risk 
as defined by the study?  If the answer is no, can the 
committee identify a subpopulation in the study for which 
the benefit-risk ratio is acceptable?  Does this demonstrate 
a favorable risk-benefit ratio for prevention of breast 
cancer in women at increased risk as defined by the study?
	DR. SIMON:  I guess in this situation I am not 
sure we should -- it is really does the treatment in this 
population of women provide a favorable benefit-risk ratio.  
You know, there may be certain benefits and there may be 
certain risks.  Here, I don't think we can change 
"prevention" to short-term incidence because it is asking a 
broader question.
	DR. DUTCHER:  Okay.  Do you want to comment on the 
question?
	DR. SIMON:  Well, I guess my own feeling is the 
answer is no.  I guess I have two concerns.  One is that 
there is some uncertainty as to what the population who 
actually achieved short-term benefit is.  The second concern 
is I think this incorporates -- when you are talking about 
risk-benefit you have to think in terms of long-term 
effects.  I think there is great uncertainty in terms of 
what the long-term mortality benefits are given that many, 
if not most of the tumors that are being prevented or 
delayed are going to be curable by surgery plus tamoxifen.  
I think you have to be concerned here when we talk about the 
risk ratio.  There are many women who could be included in 
this trial who would satisfy the eligibility criteria for 
this trial, for example, being 60 years old with no risk 
factors, for whom I think the risk-benefit ratio was not 
favorable.  I think the long-term benefits are probably 
relatively small and the risks are large, and the risks 
apply to all of the women and the benefits only apply to a 
small subset. 
	DR. DUTCHER:  Dr. Margolin?
	DR. MARGOLIN:  I happen to agree with Dr. Simon, 
but the real reason I wanted to speak is that I think if we 
are going to remove the word "prevention" -- I think we 
agree that this drug does not prevent breast cancer, or at 
least there is no evidence to date.  So, for consistency we 
would still have to reword the question:  A favorable 
benefit to risk ratio for the short-term decrease -- for 
reducing the short-term incidence of breast cancer.  That 
actually makes it a little bit easier to accept the 
risk-benefit because we are not being asked to say, yes, we 
agree that it prevents breast cancer but only that it 
reduces the short-term incidence, which is pretty obviously 
the case. 
	DR. DUTCHER:  Dr. Justice?
	DR. JUSTICE:  I just want to clarify what we mean 
by "defined by the study."  We are talking here about the 
patients who were actually entered on the study, not the 
patients who would necessarily have been eligible for the 
study, because that is the data we have. 
	DR. DUTCHER:  Okay, well, that is what we want to 
use.  Can we just say as defined by the study population?
	DR. JUSTICE:  Sure. 
	DR. OZOLS:  Do you want to make another comment 
about the length of follow-up?  Do you want to perhaps 
address the issue of the limited follow-up available?  Does 
NSABP demonstrate that tamoxifen have a favorable benefit, 
because as Dr. Simon pointed out, it is a long-term thing.  
I mean, with the data available now you are actually, I 
guess, asking us for the short-term follow-up.
	DR. JUSTICE:  That is fine. 
	DR. JOHNSON:  I actually think this is very 
important because we are talking about two different things.  
If we are going to talk about prevention, and the way the 
question is worded, I think many committee members -- and I 
am projecting now, would vote one way as opposed to if we 
changed the wording here.  I think it is important to 
understand what we are voting on, and I would personally 
argue that we should at least vote on the issue of 
prevention, and then we can modify later, if you would like, 
because I think that will have a bearing on some subsequent 
discussion that takes place.  
	DR. DUTCHER:  So your proposition is to vote on 
the question as it stands and then modify the question? 
	DR. JOHNSON:  Right.
	DR. DUTCHER:  Is that all right? 
	DR. SCHILSKY:  I think we have already sort of 
agreed by consensus that there is limited evidence for 
prevention so why go through that exercise?
	DR. JOHNSON:  Well, it may be a subtle, and it may 
seem like an arcane point but I think it is an patient 
point, and I think maybe people have discussed or attempted 
to discuss that throughout the course of the morning, not 
only on the panel but the applicant and members of the 
public. 
	I personally think it is a very important issue, 
and I think Dr. Simon's point that he has come back over and 
over again is the crux of the issue.  That is, what 
population was treated here?  If we understand that 
population very clearly, then we can judge more definitively 
the risk-benefit ratio, at least for short-term.  Prevention 
is quite different.  We have acknowledged that, and I think 
that is why it is important.  I think people may go away, if 
we don't definitively address the issue of prevention, 
thinking that we just used a code word for prevention.
	DR. DUTCHER:  Dr. Margolin?
	DR. MARGOLIN:  Well, I think we had better be very 
careful about putting too many extra words also in the 
question.  Somebody suggested, you know, talking about does 
it do it just for the short term, to the extent that the 
study was followed, or something like that.  When we commit 
to putting a woman at high risk on an intervention we are 
committing to whatever happens to this woman for the rest of 
her life, and her life doesn't stop at the same time that 
the follow-up was reported or when we took this vote. 
	DR. DUTCHER:  All right, I think we should vote on 
the question as it stands and then we will modify it.  Does 
the NSABP P-1 demonstrate that tamoxifen has a favorable 
benefit-risk ratio for the prevention of breast cancer in 
women at increased risk as defined by the study population?
	All those who would vote yes?
	[No response]
	All those who would vote no?
	[Show of hands]
	Eleven no; zero yes. 
	If the answer is no, can the committee identify a 
subpopulation of the study for which the benefit-risk ratio 
is acceptable?  I guess if the answer is no, can the 
committee identify where the benefit-risk ratio is a 
benefit?
	DR. SIMON:  I guess the way I interpret that is 
the benefit of administering tamoxifen for 5 years with the 
intention of having some anti-breast cancer effects.  Is 
there is a set of women that we can identify with that fact 
that is likely to outweigh the risks entailed by treating 
that group of women? 
	DR. SCHILSKY:  It seems to me that the intent of 
this question as modified is that I think we pretty well 
agreed that as yet there is not compelling evidence for 
prevention of breast cancer.  There may be as time goes by 
but as yet there is not compelling evidence for prevention.  
There does seem to be compelling evidence for short-term 
reduction in incidence.
	So, the issue then is can we identify one or more 
populations of women for whom the risk-benefit ratio favors 
use of tamoxifen to reduce the incidence of breast cancer? 
	DR. SIMON:  I think when you are talking about 
risk and benefit you can't stay with the short-term 
incidence of breast cancer --
	DR. SCHILSKY:  It will change over time.
	DR. SIMON:  You know, if we don't think that is 
likely to translate into some mortality benefit, then how 
can we weigh that?  You know, then it becomes a less 
meaningful thing.  So, the way I view this question is that 
there are some women who were able to at least delay, 
possibly for a very long time, possibly for ever, the 
incidence of breast cancer.  And, we have to treat a whole 
lot of women and expose all of them to risk in order to 
prevent a certain number of breast cancers in whatever 
population we are trying to identify here.  When we think 
about the risk-benefit, then we have to take into 
consideration that some of those things that we are going to 
be delaying or preventing, whatever it is, are going to be 
curable anyway.  Therefore, since I think that the reduction 
in mortality is likely to be small, the reduction of breast 
cancer mortality is likely to be small, that means that we 
need to be focusing on a quite high risk population or a 
population who are not so subject to some of the risks. 
	DR. SCHILSKY:  But the pragmatic issue is, is 
there any group of women to whom tamoxifen should be given 
today?  I think that is what we are being asked to address 
here. 
	DR. SLEDGE:  I voted no on this question because 
of the word "prevention" because we have not discussed 
risk-benefit in any meaningful sense here so far.  We all 
know what the risks are.  I think the study and other 
studies of tamoxifen give us a pretty good idea of the 
safety profile of this drug and I think that is unlikely to 
change over the next decade or two. 
	So, the real question to me here is the question 
of how do we define benefit.  Do we define benefit in terms 
of short-term incidence?  Do we define benefit in terms of a 
survival advantage?  If we are going to set that bar then, 
to be honest, we are going to have to go back as a community 
and develop an entirely new set of studies, and kind of 
pretend for the next 20 years that we don't have the results 
of P-1.  That, frankly, is a very difficult proposition for 
the oncology community.  I think that is a real problem that 
we have to be concerned with here. 
	DR. SIMON:  We know something about the survival 
rates of node-negative, ER-positive breast cancer. 
	DR. SLEDGE:  I will tell you that having buried 
several women with ER-positive, node-negative breast cancer 
I won't take quite as blas a view.
	DR. SIMON:  I am not saying it is 100 percent; I 
am saying we know something about what it is.
	DR. SLEDGE:  We know it is better than having lots 
of positive lymph nodes.  But, you know,  kind of the 
impression one gets from hearing this discussion is that if 
we add up thromboembolic events and add up endometrial 
cancer and add up cataracts, and then add up the breast 
cancer cases that you can do some sort of mathematical 
equivalency. 
	Real life is that when one goes into the clinic 
with a woman who has a multi-generational history of breast 
cancer with her sister, her mother and her aunt who died of 
breast cancer, that patient may well be willing to accept a 
different level of risk than your 60-year old who has no 
risk factors. 
	I guess the question comes down to really how do 
we define benefit here, and to what extent do we remove that 
from the bedside?
	DR. MARGOLIN:  I think in trying to identify a 
subpopulation of patients at risk to whom we can apply this 
data we have to be careful to be aware that this 
identification of risk factors is a rapidly moving target.  
BRCA 1 and 2 issues are still to be determined.  The patient 
you just described may be at risk of an ER-negative, 
node-positive tumor, or may be BRCA 1 positive or not, and 
we can't extrapolate too much from what little is known 
about the actual risk factors that were used in this study. 
	DR. ALBAIN:  I think too there is another side we 
haven't heard today.  We haven't heard the advocacy 
community on the other side of this question, and I would 
defer to our two members here.  The trauma of being 
diagnosed with breast cancer -- I don't think you can weigh 
it the same way as getting a pulmonary embolus even though 
you may, in fact, survive both of those events.  I wanted 
your comments on this issue because it is really difficult 
to try and put that into the proper perspective.  I had 
hoped, actually, to hear from the advocacy community on the 
other side because they were very involved in this trial's 
development. 
	MS. CASSEL:  I know in my risk population, having 
a mother and a grandmother that were diagnosed with breast 
cancer, ER positive, and today I hear you talk about, you 
know, mortality really isn't any different, but it is your 
quality of life of life now and you are living now.  From 
the population that I have spoken to in my similar 
circumstances, these women want a choice -- let me go to my 
doctor.  Yes, we have pulmonary emboli; yes, we have 
cataracts; yes, we have hot flashes; yes, we have 
endometrial carcinoma but let me make that choice.  As long 
as I am well-versed and the physician is well-versed and is 
honest, let me make that choice.  Let me, my family and 
physician make this choice. 
	To me, personally, I guess if you are talking 
about endometrial cancer, I can handle that personally.  
And, that is just me.  Maybe someone else can't.  I feel I 
can have more control of that by going for endometrial 
samplings, GYN visits, etc.  But it is more personal, and I 
think you need to give the women a choice. 
	But I am afraid, on the other end, that you will 
have this woman who says, "oh, okay, well, here's my magic 
pill; this will protect me.  I don't need to do my 
self-breast exam.  I can miss my mammogram.  I don't have to 
follow routine."  That does frighten me.  So, it is a mixed 
bag.  I don't think there is going to be an easy answer. 
	MS. BEAMAN:  One of my great concerns -- I 
certainly agree with Debbie -- is that when we leave here 
today we need to have a clear-cut definition of who was 
helped by this.  Who is this population?  Where can we run a 
reference and say, when we are talking to "Jane Q. Public" 
that you fall into this risk of even short term and, 
therefore, you would be a candidate for taking the tamoxifen 
for the 5 years?
	I am also very concerned about the fact that there 
is a high incidence of breast cancer after that preventive 
run of tamoxifen in women who did not have cancer before 
taking the drug. 
	Maybe we can't clear this up today but we should 
certainly not mislead anyone by voting in a positive way 
here today and leaving here, having women all over think 
that there is that magic pill and it does all of this that 
the papers have noted up to this point. 
	DR. JOHNSON:  It may be that this is simplistic 
thinking on my part, but of the patients who did develop 
invasive breast cancer on the placebo arm  -- I am sure 
NSABP has analyzed that group of women, and what do we know 
about them?  Are there any characteristics that stand out in 
that group that, in fact, developed invasive tumors as 
opposed to the other 5850 women in that arm?  I mean, was 
there something unique about that group that may have 
identified them as a higher risk, and how did that relate to 
the 86 women on the tamoxifen arm?
	DR. COSTANTINO:  There really is no 
differentiation between the level of risk of the women who 
got breast cancer and those who did not get breast cancer on 
the placebo arm. 
	But I really feel that we need to correct 
something that has been misstated here twice.  The 
misstatement is that the rate of breast cancer was greater 
in the tamoxifen arm after the drug was stopped.  That is 
not correct.  The rates were the same in the 2 arms after 
drug was stopped.  There was no rebound effect.  There was 
no additional preventive effect but there was no rebound 
effect. 
	DR. JOHNSON:  And just for clarification, if I 
may, when you say that there is no difference in these 2 
groups, that is not looking at BRCA 1 and 2.
	DR. COSTANTINO:  That is correct.  BRCA 1 and 2 
was not included.  We do not have that information as of 
yet.  It is based on the factors that went into the risk 
profiles.
	DR. ALBAIN:  Since I have apparently misstated 
something here, I think it is very important that we have 
this clarified because we have been given data that states 
that 34 cases on the placebo arm were diagnosed after 
stopping the study drug versus 39 on the tamoxifen arm.  
That is 39/85 versus 34/154.  Is this incorrect data?
	DR. COSTANTINO:  When you are calculating the risk 
of disease, it is based on the total of women who were at 
risk not just the number of individuals who got disease.  
So, it is 39/6000 versus 34 out of approximately 6000.  So, 
that is why the rates are exactly the same. 
	DR. ALBAIN:  Okay, thanks. 
	DR. DUTCHER:  Do you think we can define a 
population, or should we go on to another question and try 
to come back to this?
	DR. JUSTICE:  Well, I mean, that is the question.
	[Laughter]
	I just want to clarify.  Dr. Johnson wanted to 
vote separately on the prevention question.  Do you also now 
want to vote on the overall population, reducing the 
short-term reduction in risk?  Is that what you would like 
to do overall, and then, if the answer is no, do that for a 
subgroup?
	DR. JOHNSON:  Well, I am having a difficult time, 
based on the information that has been provided to us, to 
come up with a subpopulation.  I don't see how any of us 
could.  It would be speculation on our part.  I am sure the 
applicant is going to do a number of analyses over the next 
several months as they go through these data.  It seems to 
me the only thing we can do is vote on whether the 
population that was entered into the trial is appropriate 
for the indication or not.  That seems to me to be the only 
thing that we can do.  I think that is going to be a 
difficult vote but that is my view. 
	DR. DUTCHER:  Dr. Raghavan?
	DR. RAGHAVAN:  I think we are sort of beginning to 
set a different standard from the deliberations of the 
committee over the last few years.  In a way, maybe you 
could say that is okay because we are dealing with 
prevention issues as opposed to treatment issues.  But the 
way we have approached drugs coming through the committee 
over a period of time is that we have made our decisions 
based on the data available. 
	I have been sitting here, scratching my head for 
the last three hours, trying to figure out what the rush was 
to come to this committee because there is a wealth of 
information there.  I mean, this is a fantastic trial.  It 
has been done by one of the best groups in the world.  If we 
turn down the application I think it would be a real shame 
for anyone to interpret in any sense that it reflected on 
the NSABP.  It reflects on the judgment to come to the FDA 
at this time; it has nothing to do with the quality of the 
data as they stand. 
	I think the reality is that we are all experts in 
the field but, unlike Dr. Sledge, we don't have a prescience 
and --
	[Laughter]
	-- therefore, we can only look at the data and 
even Dr. Sledge wouldn't try to influence this committee on 
his knowledge of what will come down the pike -- quoting his 
own words back at him.
	So, I think one of the problems with the questions 
is that they were framed in advance of the meeting and we 
are now wrestling, trying to fit them into a mold that 
really we can't fit. 
	I think one of the much more interesting issues 
that we should come up with today is the question of do we 
think that another trial needs to be done?  Do we have to go 
back to square one?  I personally think not.  Or, do we need 
more data to be extracted from the trials that are extant?  
You know, we have quoted journal reports.  We are fortunate 
to have Dr. Powles here.  But essentially we have not had 
raw data to look at.  The advocates who have spoken, have 
spoken as if there is something magical in the peer reviewed 
published press, and there isn't.  I mean, the peer reviewed 
published press will often have less information than we 
have heard today.
	So, I think all we can do in the context of where 
we stand is look at the data that are on the table.  I don't 
think we should from now on for the rest of the discussion 
ask the members of the NSABP to data dredge to try to help 
us.  I think the data are on the table.  We can either make 
decisions based on those with a frame of reference that says 
we have this information out to this point.  I think the 
NSABP knows as well as we do that curves come together.  I 
think we all have a hunch that these curves won't because 
breast cancer generally doesn't adopt a zig-zag course but 
the reality is that we don't know that for a fact. 
	So, I think instead of trying to fit molds of 
questions that really may not be appropriate now, after all 
we have heard, I think we just have to look at the data that 
are available rather than trying to extract more bits of 
information in an ad hoc fashion. 
	DR. DUTCHER:  So, we could rephrase the question 
into does the study demonstrate that tamoxifen has a 
favorable benefit-risk ratio for a reduction in the 
short-term incidence of breast cancer, and that becomes the 
question.  Is the benefit-risk ratio sufficient for the 
reduction in breast cancer as observed?
	DR. SIMON:  I guess I am a little confused as to 
what that would mean, in other words, to look only at the 
incidence and not worry at all about that might translate 
into or not translate into.  I don't know, I have a little 
trouble with that. 
	I guess the other thing is the issue we are 
supposed to be talking about, "as defined by the study 
population."  You know, I think we haven't received a whole 
lot of information, at least for the women over 60, in terms 
of what that study population really looked like. 
	DR. DUTCHER:  Well, we can deal with the 
information that we have -- I mean, that is what we have to 
do, and decide whether the benefits to this group of people 
outweigh the risks as demonstrated in the study.  We have, 
certainly, the short-term risks and we have the short-term 
benefits. 
	DR. MARGOLIN:  I think that would be consistent 
with how we chose to vote on question one, and it would be a 
logical follow-on to our vote on question one.  It is just, 
you know, in women at increased risk as studied in P-1.  We 
have already given up on trying to define the subpopulation.
	DR. SIMON:  Well, at some point I think you have 
to take cognizance of the fact that if you are going to say 
something has a favorable benefit-risk ratio, then it is for 
some defined group of women and you want to make sure you 
understand what that definition is and try --
	DR. DUTCHER:  But I don't think we have enough 
information to do that.  I mean, I think we really are going 
to have to go back and look at each subgroup. 
	DR. JUSTICE:  I think that is our job, to get that 
information from NSABP, but what we are saying is based on 
the trial results, when we get that all sorted out, what is 
your recommendation? 
	DR. RAGHAVAN:  Richard, you are torturing us, as 
only a statistician can. 
	[Laughter]
	You know, the reality is that this group took 
13,000 courageous volunteers and, at the end of a lengthy 
period of time, demonstrated that those people who were 
exposed to tamoxifen for 5 years and less had less breast 
cancer, which is a good thing.  And we have asked them, and 
we have shaken them, and we have said tell us which ones you 
think are the best players, and they said, "we don't yet 
know," I think the operative word being "yet."  Maybe from 
this data set they will never know, but the answer for us 
now is "yet."  And, you are setting us to a standard that 
makes us prestigiate because the data just aren't there.
	DR. SIMON:  I mean, a prevention trial is 
different than a therapeutic trial, and basically it is 
different because relatively few proportion of women who get 
the drug benefit but, yet, everybody is subject to the risk.  
So, when you say is it worthwhile to treat all of these 
women for this benefit, it is more important than typically 
in a clinical trial, a therapeutic clinical trial, to sort 
of assess who really was subject to the risks and who really 
got the benefit, and were there women who just weren't 
studied enough, with enough numbers, to know whether they 
got the benefit or not.  If so, then you probably wouldn't 
want to believe that you really knew whether it was 
appropriate for them.
	DR. DUTCHER:  Go ahead.
	DR. MARGOLIN:  I hate to torture the discussion 
even further but in answer to Dr. Simon's concerns, we could 
only legitimately do that on pre-stratified factors anyway 
because subset analysis is not something we want to rely on 
retrospectively in any case when those factors weren't 
pre-stratified.  And, you can't pre-stratify for factors 
about the cancers that hadn't developed at the time that 
patients were enrolled. 
	DR. SIMON:  I mean, I really wasn't looking so 
much for looking at every subset that benefited.  I really 
was more looking for just a clear description of who were 
the women who got in the trial and, for example, for the 
older women who were they in terms of how may risk factors 
they had, and that sort of thing, to make sure that we have 
enough evidence that they were represented in this trial and 
that they would then be included in a recommendation.
	DR. RAGHAVAN:  The way you could get around that 
is that you could potentially vote in the affirmative in the 
phraseology that Dr. Dutcher portrayed, and then put in a 
caveat that at the present time the specific women likely to 
benefit have not yet been identified.  That could be made as 
a caveat to the vote, or you can vote no.  But you can't do 
more than that because the data just aren't there.  You 
can't speculate. 
	DR. DUTCHER:  We could put something in saying for 
women with 5 times the risk.  No?  You don't like that?  We 
could also ask the question does it demonstrate a favorable 
risk-benefit for reduction of incidence of breast cancer for 
women at increased risk as defined by the study population?  
Then, the second question could be can you define the exact 
population for which the greatest benefit exists?
	DR. SLEDGE:  I think we get into real danger when 
we subset.  I agree entirely with Derek.  We have a study 
population.  The study was not designed to look at the 
subsets with any statistical precision.  We don't have long 
enough follow-up to make those judgments even 
retrospectively.  I think we either vote it up or down for 
the study, not for the subsets. 
	DR. DUTCHER:  Okay.  With the limited follow-up 
available, does NSABP P-1 demonstrate that tamoxifen has a 
favorable benefit-risk ratio for decreasing the incidence of 
breast cancer in the patients in this study population? 
	All those who would vote yes?
	[Show of hands]
	Nine.  Nine, yes. 
	Those who would vote no?
	[Show of hands]
	Two.  Two, no. 
	The next question is dealing with the comparison 
or at least the evaluation of the other trials, the Italian 
trial and the Royal Marsden trial.  There are a couple of 
tables to look at. 
	What effects should the results of the Royal 
Marsden and Italian tamoxifen breast cancer prevention 
studies have on the approvability of the indication that the 
applicant is seeking?  If they do not affect approvability, 
should the results be addressed in the tamoxifen package 
insert and patient package insert?
	Any comments?  Dr. Simon?
	DR. SIMON:  Well, I think the Royal Marsden trial 
just highlights the fact that there are some women who 
benefit and some women who don't, and we don't know really 
at this point -- there is some population that is benefiting 
from this intervention but it is not really clear what it 
is. 
	DR. DUTCHER:  Dr. Margolin?
	DR. MARGOLIN:  Those trials were not scrutinized 
or reviewed by the FDA reviewer the way the P-1 study was, 
and I don't think they should be allowed, you know, other 
than for discussion.
	DR. DUTCHER:  Dr. Schilsky?
	DR. SCHILSKY:  I guess I just have one question 
about the wording.  Since the indication the applicant is 
seeking is use of tamoxifen for prevention of breast cancer, 
based on our discussion up until now, are we assuming that 
the wording of the indication would be changed or not?
	DR. JUSTICE:  Yes.
	DR. SCHILSKY:  We are assuming that? 
	DR. JOHNSON:  Let me just ask a question and make 
a comment.  I mean, I have heard the comments made by many 
of the public speakers and our advocates on the panel, and 
repeatedly the comment has been made that we need 
information.  These are two studies that have, in fact, 
appeared in the peer reviewed press, although perhaps not as 
heavily scrutinized as they might have been by the FDA and I 
will grant Dr. Raghavan's comment that the peer review 
process may not be quite as stringent as the FDA ODAC 
process, certainly not as tortuous, but, nevertheless, they 
have been reviewed and I do think those are data that, at 
least if I were thinking about going into a trial onto a 
drug, or if my wife were or my daughter, I think it would be 
good for them to have that information.  So, the fact that 
it is in peer reviewed literature would certainly make me 
comfortable including it.  I don't feel impelled to include 
it but I think I would feel comfortable including it. 
	DR. JUSTICE:  We would certainly characterize it 
as having been reported, not as having been reviewed. 
	DR. DUTCHER:  I would also like to say I agree 
with Dr. Simon's interpretation which just focuses more 
clearly that we don't know who to treat, even if we think 
there is something positive happening here.
	DR. JOHNSON:  Well, I think that is what these 
data show.  Distinctions are made in this type of table.  
Admittedly, it may be fairly sophisticated for the average 
physician, let alone the average lay person, to try to 
distinguish all of this information but, nevertheless, it is 
there.  One can refer to it; one can compare and contrast, 
and understand that there, in fact, is a difference.  
Furthermore, I think it gives a lot of credibility to the 
P-1 trial based merely on the size of the trial.  I mean, 
there is so much there that is useful, it seems to me, that 
it is worth including it.
	DR. SLEDGE:  I would agree with David.  I don't 
think this alters the approvability or non-approvability but 
I think it is certainly reasonable information to include in 
the packet. 
	DR. DUTCHER:  All those who would vote yes on 
question three?
	DR. SLEDGE:  Which part?
	DR. DUTCHER:  We want a yes/no question.  Should 
the results of the Royal Marsden and Italian tamoxifen 
breast cancer prevention studies have an effect on the 
approvability of the indication that the risk reduction of 
breast cancer indication --
	DR. JOHNSON:  I wonder, rather than voting on 
this, if it might not be worth just getting the sense of the 
panel?  My personal view is that I think we have heard from 
Dr. Powels, and we have seen and read these two manuscripts 
from the published data, I think as has been pointed out 
earlier by someone we were asked to address the data 
presented to us.  We have not scrutinized these data nearly 
to the extent that the data that we are currently 
deliberating has been reviewed. 
	So, in my view the answer to the first part should 
be no.  I don't think it should have an impact unless we had 
that data set to review in the same kind of detail.
	The answer to the second part, however, is given 
the fact that these data are in peer reviewed press, it 
seems to me it is appropriate to include them as 
information, as Dr. Justice has pointed out, in the package 
insert. 
	DR. JUSTICE:  Yes, I think if that is the sense of 
the committee, it is fine with us. 
	DR. DUTCHER:  Fine.  Question number four, should 
tamoxifen be approved for the prevention of breast cancer in 
women at increased risk as defined in the study or as 
identified in the answer to question two?
	Do you want to vote on this or do you want to get 
rid of "prevention?"  We are going to get rid of 
"prevention." 
	Should tamoxifen be approved for risk reduction of 
short-term incidence of breast cancer in women at increased 
risk as defined in the study? 
	DR. ALBAIN:  Would you read that again?
	DR. DUTCHER:  Should tamoxifen be approved for 
risk reduction of short-term incidence of breast cancer in 
women at increased risk as defined in the study?
	DR. SIMON:  Could we change to as defined by the 
study population rather than in the study?
	DR. DUTCHER:  All right, as defined by the study 
population. 
	DR. SIMON:  And, I guess that puts an onus on the 
FDA to figure out what that is. 
	DR. DUTCHER:  Well, it seems to me that this is a 
question where we could also put in something about defining 
an appropriate study population.  I think we are back to 
where we were. 
	DR. JUSTICE:  I think what we would like you to do 
is vote on the overall question and then, if the answer is 
no, if you think there is a population that you can vote yes 
for, cope with that.
	DR. DUTCHER:  Either a population or level of 
risk. 
	DR. JUSTICE:  Either.
	DR. SIMON:  I mean, I personally am very 
comfortable with your proposal that we say something about 
for women at high risk, or even to put in a relative risk. 
	DR. SLEDGE:  Again, this gets back to the 
subsetting issue.  I am very uncomfortable about subsetting 
on this.
	DR. SIMON:  It is not an issue of subsetting.  It 
is an issue of saying there is an overall effect but, if 
your relative risk isn't high, then the risk-benefit ratio 
is not favorable. 
	DR. SLEDGE:  I understand, but we don't have the 
data to give us a cut-off.  I mean, are you going to use 2.1 
percent, 3 percent?  If you have that data -- I haven't 
heard it today -- that would allow me to make that decision.
	DR. JOHNSON:  George and I may agree on this.  
Even though we are not sitting next to one another, we are 
not sending secret signals to one another.  I agree.  On the 
other hand, it also suggests that I have a knowledge of the 
risk that I am not subject to that would allow me to decide 
to take the drug.  In fact, it seems to me that an 
individual who is being asked to take the drug has to decide 
whether that is an appropriate risk or not.  Therein lies 
the conundrum that we are faced with.  What the data have 
said is that at least at this level of risk and beyond, 
whatever that might be, in the totality of the way the study 
was conducted there was a reduction in the incidence of 
breast cancer.  So, beyond that it is very difficult for me 
to distinguish now, and my risk of getting shot walking down 
the street in Nashville is probably a little less than 
somebody walking down the street in New York.  I am not 
banging New York --
	[Laughter]
	-- the point is they are different.  I accept that 
risk and some people accept that risk living in New York.
	DR. DUTCHER:  In the Bronx.
	DR. JOHNSON:  Yes, okay, it is higher.
	DR. DUTCHER:  But on the other side of it, if we 
can't decide making a patient decide or a subject decide 
isn't fair at all.  And, if I am going to be giving them 
cards that tell them what their risk for breast cancer is -- 
I mean, I don't think that is fair either.  I think we have 
to somehow, in our own minds, be able to say, you know, 
"here's where you fit into this spectrum, and here's your 
risk of PE and here's your risk of breast cancer."
	DR. JOHNSON:  No, we are exactly agreeing.  My 
point is I don't think we can do that.  George has pointed 
out that we have a tremendous amount of information about 
the side effects of this drug and that this trial, if 
anything, confirms our knowledge of the side effects of this 
drug.  So, that was good.  We didn't find something totally 
unexpected.  There was nothing here that wasn't known about 
this drug vis-a-vis side effects. 
	What we did find, however, was that in a group of 
women at a level of risk or beyond there was a reduction in 
the frequency of breast cancer.  We did learn that.  There 
were certainly lots of side effects.  There were side 
effects in the placebo arm as well.  I think all we can say 
is that for that level of risk or beyond we can approve this 
drug or not for that indication. 
	Now, if we want to go further and say, well, in my 
mind you have to have not 1.66 but 3.0 or 5.0, well, that 
bothers me.  I mean, as a committee we have decided many 
times before that we want to give full information to the 
patient, allow the patient and the physician to make the 
decision at what level of risk he or she may wish to take 
this medication.  It seems to me that we should not 
artificially set that bar.  We should use the data that has 
already set the bar, for whatever reason that was selected, 
and use that and then allow the patient to have that 
information.
	DR. DUTCHER:  Dr. Schilsky?
	DR. SCHILSKY:  Yes, I agree with David.  You know, 
I think the problem is that at any point where we would set 
the bar would be artificial.  If you go around this table 
and ask people to define which population you think has the 
optimal risk-benefit ratio, you are going to get a different 
answer from each of us, undoubtedly.  That just reflects the 
fact that there is going to be a different ratio in every 
doctor-patient encounter when this is brought up for 
discussion. 
	So, I think it is probably unwise for us to try to 
specify in the context of this discussion some ratio.  You 
know, I am very sensitive to many of the remarks that were 
made by members of the community at large about concerns 
that busy doctors are not going to have time to adequately 
discussion these things with patients, and that hysterical 
patients are going to be out there demanding tamoxifen, but 
I think, nevertheless, it is incumbent on the medical 
community, on the patient advocacy groups, and all who are 
involved to devote their energies to educating patients and 
physicians about how to determine risk and benefit in this 
sort of circumstance, and then let those discussions between 
doctors and patients go forward. 
	DR. DUTCHER:  Dr. Ozols?
	DR. OZOLS:  I agree that I think this is not 
unique to this drug or this situation.  I think physicians 
very frequently discuss risk-benefit ratios for all sorts of 
treatments, and it ultimately comes down to a decision 
between the patient and the doctor.  I think we aren't going 
to be able to say that at some level you must take this drug 
because that is not going to be the case.  So, I think we 
need to have that option for the patients and the physicians 
to be able to discuss that and then come to an individual 
decision. 
	DR. DUTCHER:  But I also do think, as was brought 
out, that physicians in different fields have different 
perspectives on the risks.  For example, if you talk to a 
gynecologist about hormone replacement or an oncologist 
about hormone replacement therapy you may get two different 
perspectives.  So, I don't know that oncologists, in terms 
of assessing risk-benefit or discussing it are going to be 
the people that will be discussing it with subjects or with 
people that would get tamoxifen, frankly, and I think that 
is where the educational aspects have to come in, in terms 
of people that have cancer phobia, saying everyone should 
get a drug that has clearly a risk-benefit ratio that varies 
with the patients or the subjects that are getting the drug.
	DR. SCHILSKY:  I do think that is a critically 
important point because I think essentially all of us around 
the table are medical oncologists.  In fact, you know, we 
may be participating in counseling some patients but we are 
not likely to be prescribing this drug for this indication a 
whole heck of a lot because, you know, the candidates for 
this are people who don't have cancer.  So, they are not the 
ones who are coming to see us with great frequency, and they 
are going to be seen in the community by private 
practitioners, by generalists, by OB-GYNs and so on, and 
their perspectives and the importance of educating them 
about this issue I think has to be paramount.  So, we need 
to just send the message that we think the risk-benefit is 
beneficial for women who are at high risk of breast cancer.
	DR. SLEDGE:  Actually, I would like to add 
something to what Dr. Schilsky said.  I generally think this 
is a drug that should be approved because I think doctors 
and patients should be allowed to decide this issue on an 
individual basis. 
	Having said that, I am tremendously concerned 
about how it is going to be used, and I think for a 
chemoprevention drug, however so defined, there probably 
should be a higher bar in terms of doctor-patient 
communications, specifically in terms of the onus on the 
company and on the NCI's chemoprevention branch to provide 
information to patients about this.  I suspect this has 
never been done, but I would be quite happy making my 
recommendation dependent upon real evidence that the NCI and 
the company are going to put real resources into patient 
education and doctor education on this issue. 
	DR. ALBAIN:  I was just going to say the same type 
of thing.  The sponsor has an incredible and exciting 
challenge here to be the first out there with this type of 
approval for breast cancer prevention, and really doing this 
education process, getting out to the primary care 
societies, to the gatekeeper physicians who will be seeing 
this type of patient. 
	DR. RAGHAVAN:  As a coda to that, I think there is 
a  very substantial responsibility to develop a mechanism 
for following these patients as well because that is clearly 
what we are all worried about, and that is what the advocacy 
groups have said.  They don't want, and we don't want to see 
any patients developing a whole series of complications 
late. 
	Now, that puts a big responsibility on the sponsor 
because that sort of thing costs money.  I guess what that 
says is that the FDA, the sponsor and the NCI 
chemoprevention branch need to figure out a mechanism.  That 
is not our role here.  I think our role is to identify what 
the problems could potentially be, and I think we all 
recognize the benefits that NSABP have shown out to 5 years.
	We are stuck with the fact that there is a whole 
alternative lobby out there who never bring their products 
to the FDA that patients in this situation use every day of 
the week.  We, as a group, probably underestimate 
outrageously some of the products that have really 
substantial complications.  So, we don't want to set the bar 
to a level where tamoxifen, with FDA, NCI, NSABP and anybody 
else's blessing is being kept away from patients when all 
sorts of other more dangerous products are available.  At 
the same time, we don't want to sanction this and then in 20 
years say, "boy, have we got a lot of complications that 
we've only just discovered!"  So, there needs to be a 
mechanism for monitoring I think if we let this through. 
	MS. CASSEL:  What I envisioned was going to my 
primary physician, and a decision is made to take the 
tamoxifen.  I envision then being put into a database with 
the sponsor, being followed up with adverse events that the 
physician and the patient knew were serious or questionable 
and then being given follow-up newsletters periodically.  
So, you are kept in a database and that you are well versed.
	DR. DUTCHER:  You envision this because you 
thought it was a good idea or someone told you this would 
happen?
	MS. CASSEL:  This is what my blue-sky vision would 
be for this compound. 
	DR. DUTCHER:  Has the sponsor considered a 
registry of tamoxifen prevention people? 
	DR. JOHNSON:  Where I live people try to avoid 
being in databases like that.
	[Laughter]
	MS. BEAMAN:  I think that it would, indeed, be a 
blue-sky event.  I am a representative of a population that 
when there is a breast exam or a gynecological evaluation 
the patient goes to see the OB-GYN.  Then, when that happens 
and you tell them that, you know, "my mom had breast cancer 
and I know that now I can get it," or, "I've heard of it," 
and a prescription is written.
	DR. DUTCHER:  Period.
	MS. BEAMAN:  That is it.  There is no follow-up.  
There is no nothing.  And we are going to see a major 
blow-out; a major blow-out in that particular population.  
There is no database.  There will be no follow-up.  
Sometimes the follow-up doctor visits can be the difference 
between paying rent or not following up on something that 
could be a very positive indication of uterine cancer or 
something.  But, at the same time, who are the people who 
were helped?  If we clearly define that, then those are the 
people who will benefit from this particular data. 
	DR. DUTCHER:  Dr. Justice?
	DR. JUSTICE:  I would just like to comment that we 
have clearly gotten the message that an extra special 
education campaign needs to be undertaken, and we will work 
with Zeneca to see what they are willing to do if you vote 
yes on the question.
	DR. DUTCHER:  If what?
	DR. JUSTICE:  If you vote yes on the question, 
obviously. 
	DR. DUTCHER:  Okay.  Are you ready to vote?  No?
	DR. SIMON:  It says increased risk.  Can we say 
high risk? 
	DR. DUTCHER:  But we haven't defined high risk.
	DR. SIMON:  Increased means anything greater --
	DR. DUTCHER:  No, it says increased risk as 
defined by the study population. 
	DR. JUSTICE:  Yes, I think our intent is to 
characterize the risk in that population and put it in the 
labeling, and so it will be indicated. 
	DR. DUTCHER:  You will put tables in?
	DR. JUSTICE:  We will put as much information in 
there as we can fit.
	DR. DUTCHER:  Should tamoxifen be approved for 
risk reduction of the short-term incidence of breast cancer 
in women at increased risk as defined by the study 
population?
	All those who would vote yes?
	[Show of hands]
	Nine.  Nine, yes.
	Those who would vote no?
	[No response]
	Those who abstain?
	[Show of hands]
	Two. 
	Okay.  Question five, in the study participants 
were required to have a history and physical examination, 
blood tests including CBC and chemistries, renal function 
and liver function, gynecologic exams including pelvic and 
Pap smear, at baseline.  Women were required to have had a 
normal mammogram within the past 6 months.  After study 
entry, a physical examination, breast examination and blood 
tests were performed at 3 and 6 months and then every 6 
months.  yearly mammograms and gynecologic evaluation, as 
defined at baseline, were required. 
	Does the committee recommend that the package 
insert and patient package insert should include all of the 
above protocol-specified monitoring? 
	Go ahead, Dr. Ozols.
	DR. OZOLS:  Yes, I think the gynecologic exam and 
physical exam certainly should be continued.  I don't see 
any indication that you need all the blood tests. 
	DR. SLEDGE:  And a mammogram obviously.
	DR. JOHNSON:  Unless the applicant tells us that 
they have looked at that data and they have seen something 
that would be unique for that study -- presumably no. 
	DR. DUTCHER:  Do you want us to actually vote on 
that question?
	DR. JUSTICE:  You don't need to vote. 
	DR. DUTCHER:  Okay.  Revised question six, 
endometrial sampling at baseline and annually was added as a 
protocol amendment.  Four thousand three hundred forty-five 
women were screened from 1 to 5 times; 26/47 women with 
endometrial cancer had at least 1 endometrial sampling.  One 
comparison that could be made is shown below.  You can see 
the table. 
	The detection rate on a per patient basis, not per 
sampling, was similar with or without endometrial sampling.  
Twelve women, 0.28 percent of women with sampling, were 
found to have endometrial cancer on sampling; 4 were 
randomized to placebo and 8 were randomized to tamoxifen.  
Six of these women, 0.14 percent of women with sampling, had 
no antecedent signs or symptoms and diagnosis of their 
endometrial cancer might have otherwise been delayed.  Four 
of the 6 were found to have endometrial cancer on routine 
sampling, and the other 2 were found to have complex 
atypical hyperplasia, which was treated with hysterectomy 
and endometrial cancer was found incidentally during 
pathology review. 
	Based on the information from this study, should 
the package insert and patient package insert recommend that 
women who take tamoxifen for the short-term reduction of 
breast cancer incidence undergo yearly endometrial sampling?
	DR. SLEDGE:  No.  This is the "OB-GYN employment 
act of 1998!"
	[Laughter]
	DR. DUTCHER:  What do you think is sufficient?
	DR. SLEDGE:  My review of the literature is we 
have nothing other than the patient's symptomatology that 
really represents a reliable indicator of whether or not the 
patient is likely to have endometrial cancer, and to mandate 
a procedure that is of unproven benefit I think would be 
enormously expensive and would not save any lives. 
	MS. CASSEL:  You don't think it should be done as 
screening as entry criteria?
	DR. SLEDGE:  No, I do not.  I mean, we are talking 
about a low -- you know, this is given as a per patient 
rate.  The real question is on any given sampling what is 
the likelihood of finding endometrial cancer, and the answer 
is that it is infinitesimally small.  So, you are doing a 
huge number of samplings to get a very tiny benefit, if that 
benefit is real in terms of early detection of endometrial 
cancer, which we don't know.
	MS. CASSEL:  Unless it is you --
	DR. SLEDGE:  I have no objection to a patient 
requesting it, and I have no objection to someone ordering 
it.  I am saying to mandate it in the absence of any data 
that it is beneficial I think would be very unfortunate.
	DR. RAGHAVAN:  Yes, I agree with George, and I 
think the NSABP presentation gave some data, as I recall, a 
couple of days ago when they first started to speak --
	{Laughter]
	-- that they were, (a) dropping it from their 
future protocols and, (b) it was a rationally-based decision 
that had to do with the pick-up rate from the procedure.  
They may want to comment on that now but that was my take 
from either Dr. Wolmark or Dr. Costantino, that didn't 
influence staging. 
	DR. DUTCHER:  All right.  So, all those who would 
vote yes on question number six, that women should undergo 
yearly endometrial sampling?
	[No response]
	Zero.
	All those who would vote no?
	[Show of hands]
	Nine, yes.
	All those who abstain?
	[Show of hands]
	Question number seven, in the P-1 trial, women on 
tamoxifen had a higher incidence of cataract formation and a 
higher rate of cataract surgery.  Information about 
non-cataract ophthalmologic toxicity was not collected.  
Should the package insert and patient package insert 
recommend that women who take tamoxifen for the prevention 
of breast cancer undergo yearly eye examinations? 
	DR. SLEDGE:  Again, no.  I mean, first, I didn't 
get a good sense from the data about when these cataracts 
developed, how many years you had to be on study, or 
whatever, for the average cataract to develop.  Secondly, we 
are not talking about someone losing their eyesight here; we 
are talking about someone needing cataract surgery in a 
small percentage of the cases.  You know, the indication for 
cataract surgery in many cases is that the patient notices a 
change in vision, not just simply the development of 
cataracts, as was clear in this trial where, I guess, a 
fifth of the patients who had cataracts actually went on to 
cataract surgery. 
	DR. DUTCHER:  Dr. Albain?
	DR. ALBAIN:  There was additional data from the 
B-14 population too that did show an increased incidence of 
posterior lens opacity, which is a rare type of cataract, 
and I am just wondering if we ought to consider recommending 
at least a baseline eye evaluation before women go on the 
drug. 
	DR. DUTCHER:  You want that in the package insert?
	DR. ALBAIN:  Yes.
	DR. DUTCHER:  Dr. Margolin?
	DR. MARGOLIN:  Just as a modification of that, 
even though the numbers were hugely higher in postmenopausal 
women, that is where the p value was highly significant, and 
since postmenopausal women have a higher incidence of any 
kind of eye problems maybe it would be prudent to recommend 
at least a baseline eye evaluation, and then p.r.n. in that 
population of patients.
	DR. DUTCHER:  Dr. Schilsky?
	DR. SCHILSKY:  I guess I am not convinced that it 
is worthwhile to put this in the package insert.  You know, 
if the postmenopausal women in this study are anything like 
my mother, they go to the eye doctor about every three 
weeks, anyway.  But I think that the real issue in my mind 
is whether you are going to take any action based on the 
test results.  You know, if you have a baseline test that 
shows some cataract formation, I don't know whether that 
would influence a decision whether to go ahead with the 
treatment or not.  Furthermore, if you had a follow-up test 
that showed cataract formation, I doubt that would result in 
your discontinuing the therapy.  So, I would feel 
comfortable making the risk known without making the 
recommendation for the exams to be done, and just basing the 
need for exams on symptoms. 
	DR. DUTCHER:  I don't think we can actually 
legislate when people go to a physician before they start a 
medication, and it may add an expense that is unnecessary.  
But I do think that the awareness should be there that it is 
a potential problem and that people need to know that they 
have to evaluate new changes in their vision or other 
factors. 
	All right, we will vote.  Any other comments?  All 
those who would recommend putting a baseline ophthalmologic 
evaluation prior to starting tamoxifen in the package 
insert?
	[No response]
	All those who would vote yes?
	[Show of hands]
	All those who would vote no?
	Ten.  Abstain?
	[One hand raised]
	One. 
	Question eight, does the committee have any other 
recommendations for monitoring the safety of women taking 
tamoxifen for short-term breast cancer risk reduction?
	I think we have made a lot of recommendations in 
that respect, and I think seriously people are very 
concerned that we are sort of opening Pandora's box here but 
it may be a beneficial opening for several people, and 
others have to be aware.  So, I think we want a strong 
recommendation for an educational program for both primary 
care physicians as well as subjects.
	Any other recommendations from the committee 
members?  Any specific testing you think should be required? 
I guess part of that is that we would definitely like some 
further teasing of the data.  Yes?
	DR. RAGHAVAN:  One test that may just bear a 
moment's discussion -- I don't want to prolong the agony -- 
was raised by one of the advocates, the issue of pregnancy 
and tamoxifen.  In general terms, I think once you are on 
tamoxifen, if one is looking at level of risk, the chance of 
becoming pregnant is relatively small.  But the one issue 
that might be worth considering is that before starting 
tamoxifen in a woman of child-bearing years it may be 
appropriate to consider a pregnancy test before that 
medication is started.  Certainly, if it were one of my 
family I would feel more comfortable if that were done.
	DR. DUTCHER:  Any other suggestions?
	Question nine, should FDA ask for a Phase 4 
commitment to further study participants with thromboembolic 
events for possible predisposing factors, such as Factor V 
Leiden, as Dr. Schilsky mentioned?
	DR. SCHILSKY:  Sure. 
	DR. DUTCHER:  Yes.  How many officially yes?
	[Show of hands]
	You want to ask a question?
	DR. MARGOLIN:  It probably doesn't belong here, 
but is it true what one of the patient advocates said, that 
patients from the placebo group of P-1 are being routed into 
the STAR trial so that we are going to lose the follow-up in 
those patients?  Because that sort of affects the answer to 
this question about follow-up on a large captive group of 
patients.  It would be hard to get Factor V Leiden on a 
bunch of patients off-study who were being followed, despite 
Miss Cassel's fancy. 
	DR. WICKERHAM:  We will, indeed, be allowing women 
who choose, rather than going on tamoxifen off trial, the 
opportunity of entering a follow-up prevention trial where 
they would have the opportunity to receive either tamoxifen 
or raloxifene depending on the randomization and, thus, 
contribute to that trial as they have contributed to the P-1 
study. 
	DR. SCHILSKY:  Kim, just a point of information, 
the CALGB is about to begin a case-control study looking at 
frequency of Factor Leiden in women who clot and don't clot 
on tamoxifen, and would be happy to look at samples from 
women who participated in the breast cancer prevention trial 
as well. 
	DR. WICKERHAM:  Indeed, Dr. Schilsky, Dr. Garber 
and her associates have already made that offer to us and we 
have it under review, and plan to move forward with it as 
soon as possible. 
	DR. ALBAIN:  Could I ask a question just in 
general about the further study and the participants?  What 
exactly is the follow-up that is funded so far?  Is there a 
chance for longer-term follow-up perhaps, given some of the 
comments that we have made today?  What is the current 
follow-up planned? 
	DR. FORD:  The current follow-up plan is to follow 
the women in the trial for another 2 years at the level of 
follow-up that they have had for the first 5 years, which 
includes every 6-month visits and the rest.  We had made a 
commitment from the beginning to attempt to do lifetime 
follow-up but for that, of course, you have to get into more 
of a passive follow-up mode.  We will be discussing that as 
this trial winds down, the other one starts, and what 
information we continue to get from that follow-up.  But we 
are committed to following these women for as long as it is 
possible to follow them. 
	DR. DUTCHER:  And they will be in the NSABP 
database so there will be follow-up, telephone follow-up, 
whatever. 
	Were there any no responses on question number 
nine?  All yes?  Anyone abstaining? 
	Number ten, should FDA ask for a Phase 4 
commitment to further study women on tamoxifen for 
non-cataract ophthalmologic toxicity, which could be 
incorporated into a subsequent trial?
	Comments? 
	DR. SLEDGE:  I don't have a good sense of this, 
other than I thought I heard the data presented earlier 
today to say that there wasn't an increased incidence. 
	DR. DUTCHER:  What are you referring to in this 
question?
	DR. HONIG:  I think the question was that in this 
trial the follow-up specifically collected for 
cataract-related events and also macular degeneration, but 
other eye events were not collected, especially because the 
participants weren't specifically followed for other eye 
events. 
	DR. SLEDGE:  I am sorry, macular degeneration was 
followed?
	DR. HONIG:  Right.  Incidence of macular 
degeneration on study was collected. 
	DR. SLEDGE:  It is hard to have an ophthalmologist 
look at your macula without noticing some other things.  So, 
I guess the question is what other examinations are you 
going to ask them to do?
	DR. HONIG:  Well, the question was that since it 
wasn't required, participants filled out a form.  So, you 
were dependent on, you know, hopefully, that they reported 
those visits but if they were simply told by their 
ophthalmologist that everything was all right you could 
potentially miss various events.  The question is, you know, 
do you think the trial is large enough, with the other 
published data from B-14, that this is really not an issue 
any more, or do you think there should be more information 
systematically collected on other eye findings?
	DR. DUTCHER:  Dr. Margolin?
	DR. MARGOLIN:  Could you clarify the last part of 
the question?  Would a retrospective sub-study be just to 
cull more information from the eye exams of those 
participants who had them, because otherwise those patients 
are crossing over or otherwise going on intervention.
	DR. JUSTICE:  Clearly crossover is a problem.  You 
know, I don't have a study design in mind.
	DR. MARGOLIN:  So, you are looking for just 
getting more data onto the case report forms --
	DR. JUSTICE:  Right.  Susan can correct me, but I 
think the data we have in the database is primarily 
cataracts and macular degeneration.  We do not have the 
actual data from ophthalmology exams.  I assume that NSABP 
has but we haven't clarified that yet, I don't believe, have 
we, Susan?
	DR. HONIG:  No.  We asked NSABP.  There were 
places on the form were participants could write in other 
problems or other therapies.  So, that was on the form but 
it was our understanding that was not put in the database.  
Is that correct?
	DR. COSTANTINO:  Actually, the nurses were asking 
the participants and they were filling out the forms for 
them, but that is correct.  There are places where other 
things are written in and, actually, the information was 
coded according to diagnosis of ICADA codes and we didn't 
see any differences in some of these other things.  The 
information was collected routinely on all participants and 
we felt that the information we had was adequate to address 
the question. 
	DR. JUSTICE:  But just to clarify, we don't have 
information on the actual eye exams.
	DR. COSTANTINO:  No, we do not.  We did not 
require documentation of physician reports.  We did require 
documentation of the surgeries but not of the actual eye 
exams. 
	DR. DUTCHER:  All those who would feel that 
further ophthalmologic evaluation is necessary of the study 
participants, please raise your hand.
	[No response]
	All those who would vote no?
	[Show of hands]
	Eleven, no. 
	I think the Phase 4 information that we want is 
the long-term follow-up data, and the data in the various 
subsets, and perhaps what happens to younger patients that 
are taking tamoxifen, which wasn't really discussed.  We 
would like that information to be followed up.
	DR. JUSTICE;  I would just like to thank everyone 
for dealing with this very difficult application.
	DR. DUTCHER:  Thank you for an excellent trial.  
All right, we are going to have a very quick lunch.  Can we 
do it in half an hour -- 2:45.
[Whereupon, at 2:05 p.m., the proceedings were 
recessed, to be resumed at 2:45 p.m.]

AFTERNOON PROCEEDINGS
Call to Order and Introductions
	DR. DUTCHER:  I appreciate everyone's patience; we 
have had a long morning.  We are discussing Herceptin this 
afternoon so we have a large number of new people at the 
table so we are going to again introduce the members of the 
committee.
	I am Dr. Janice Dutcher, from Albert Einstein 
Cancer Center, in New York, medical oncologist. 
	DR. O'LEARY:  Timothy O'Leary, Armed Forces 
Institute of Pathology, and I am a pathologist.
	DR. MARGOLIN:  Kim Margolin, medical oncologist, 
City of Hope, Los Angeles, California.
	DR. MILLER:  Carole Miller, Johns Hopkins, 
consultant from the CBER advisory committee.
	DR. SCHILSKY:  Richard Schilsky, medical 
oncologist, University of Chicago.
	DR. DOROSHOW:  Jim Doroshow, medical oncologist, 
City of Hope, Los Angeles.
	DR. TEMPLETON-SOMERS:  Karen Somers, Executive 
Secretary to the ODAC, FDA.
	DR. WEISS:  Jim Weiss, from Johns Hopkins.  I am a 
cardiologist and a consultant for the committee.
	MS. ZOOK-FISCHLER:  Sandra Fischler.  I am a 
patient rep.
	DR. VOSE:  Julie Vose, from the University of 
Nebraska and Chair of the FDA Biologics Committee.
	DR. LIPSCHULTZ:  I am Steve Lipschultz.  I am a 
cardiologist at the University of Rochester.
	DR. STEIN:  Katie Stein, Division of Monoclonal 
Antibody, CBER, FDA.
	DR. JERIAN:  Susan Jerian, a clinical reviewer, 
FDA.
	DR. KEEGAN:  Patricia Keegan, Division of Clinical 
Trials, FDA.
	DR. SIMON:  Richard Simon, National Cancer 
Institute.
	DR. SEIGEL:  Jay Seigel, Office of Therapeutics, 
FDA.
	DR. DUTCHER:  We have a conflict of interest 
statement to be read.
Conflict of Interest
	DR. TEMPLETON-SOMERS:  The following announcement 
addresses the issue of conflict of interest with regard to 
this meeting and is made a part of the record to preclude 
even the appearance of such at this meeting. 
	Based on the submitted agenda for the meeting and 
all financial interests reported by the participants, it has 
been determined that all interests in firms regulated by the 
Center for Drug Evaluation and Research which have been 
reported by the participants present no potential for a 
conflict of interest at this meeting, with the following 
exceptions:
	Dr. Robert Ozols, Dr. Kathy Albain and Dr. David 
Johnson are excluded from participating in today's 
discussions and vote concerning Herceptin.  In addition, Dr. 
Derek Raghavan, Sandra Zook-Fischler, Dr. Kim Margolin, Dr. 
Victor Santana, Dr. James Doroshow and Dr. James Weiss have 
been granted waivers which permit them to participate fully 
in all matters concerning Herceptin.
	A copy of these waiver statements may be obtained 
by submitting a written request to the FDA's Freedom of 
Information Office, Room 12A-30 at the Parklawn Building. 
	In addition, we would like to disclose for the 
record that Dr. Derek Raghavan and Dr. Richard Schilsky have 
interests which do not constitute a financial interest in 
the particular matter within the meaning of 18 USC 208 but 
which could create the appearance of a conflict.  The agency 
has determined, not withstanding these interests, that the 
interest of the government in Dr. Raghavan's and Dr. 
Schilsky's participation outweighs the concern that the 
integrity of the agency's programs and operations may be 
questioned.  Therefore, Dr. Raghavan and Dr. Schilsky may 
participate fully in today's discussion and vote concerning 
Herceptin.
	In the event that the discussions involve any 
other products or firms not already on the agenda for which 
an FDA participant has a financial interest, the 
participants are aware of the need to exclude themselves 
from such involvement, and their exclusion will be noted for 
the record. 
	With respect to all other participants, we ask in 
the interest of fairness that they address any current or 
previous involvement with any firm whose products they may 
wish to comment upon.  Thank you.
	DR. DUTCHER:  We would also like to note that Dr. 
Trevor Powles is going to be joining us at the table as a 
consultant for this particular topic. 
	As I mentioned this morning, we have extended the 
open public hearing to include speakers before the 
presentations and one speaker after the presentation by the 
FDA so that we can give as many interested parties as have 
requested to participate time to participate.  We are going 
to begin this afternoon's open public hearing.  We are going 
to be alternating letters with speakers, and I will let Dr. 
Somers let you know who everybody is. 
Open Public Hearing
	DR. TEMPLETON-SOMERS:  The first letter is from 
Alice Hamele, from Farmington Hills, Michigan. 
	Because I cannot travel to Rockville to be present 
at the September 2 meeting, I send these comments and ask 
that they be read and included in the docket for the 
meeting.
	I have metastatic breast cancer and tested highest 
positive for the HER2 abnormality.  After carefully reading 
the National Institutes of Health booklet on clinical 
trials, and after carefully reading the Genentech informed 
consent, I was randomized into the Genentech trial on 
February 24, 1997 to receive the HER2 antibody as well as 
the Adriamycin.  Within four months a MUGA scan revealed 
damage to my heart muscle, and heart dysfunction had been 
noted symptomatically prior to the scan.
	There was some small suggestion of heart risk in 
the informed consent dated November 21, 1996, which I 
signed.  However, it was suggested that preexisting disease 
might be the problem.  Genentech continued to collect and 
monitor data and, although these were very serious side 
effects, and although there must have been increasing 
indications that the antibody-Adriamycin combination was the 
culprit, there was no further warning or suggestion of the 
real problem as of February 24, 1997, when I was enrolled in 
the trial.  I was enrolled and consented on data that were 
three months old.  Genentech did get around to issuing a 
stronger warning, as an addendum to the informed consent, 
stating that heart dysfunction was common but, not until May 
29, 1997, did NIH declarations state that trial participants 
will receive ongoing information.  It took six months for 
Genentech to provide ongoing adverse information to 
participants -- too late for me and, no doubt, for other 
women. 
	Breast cancer patients like myself, who entered 
without complete information, now have disabling heart 
dysfunction as a cost.  And, perhaps a greater cost is that 
once "poisoned" by the Herceptin-Adriamycin combination, we 
will never be able to use the antibody agent again to try to 
extend our lifetimes.  We have the worst of both worlds.
	I ask that the advisory committee not give 
approval for Herceptin until such time as Genentech 
addresses, and agrees in writing, to deal with the costs of 
all the breast cancer women who have suffered heart damage 
because complete information was not made available to them 
when they entered the trial.  Thank you for consideration.
Sincerely yours, Alice Hamele, Farmington Hills, Michigan. 
	This and the other letters that have been received 
from the public are available for you to view at the 
registration desk.  Thank you.
	DR. DUTCHER:  I will now ask Rosemary Locke to 
please come to the podium.  We would like to ask all 
speakers to identify themselves and any sponsorship by the 
sponsor or other organizations for their participation. 
	MS. LOCKE:  Good afternoon.  I am Rosemary Locke, 
a volunteer for Y-Me National Breast Cancer Organization.  
Thank you for this opportunity to make a statement.
	Y-Me is most encouraged by the results from the 
clinical trials using Herceptin.  This is a drug that was 
developed from the growing knowledge of how cells, 
particularly breast cancer cells, function.  While indicated 
for only 25-30 percent of all breast cancer patients, 
Herceptin is the first biological agent to show favorable 
clinical results in slowing the progression of metastatic 
breast cancer, but we are also cautious since more research 
will be needed to answer questions of long-term 
effectiveness.  In addition, we believe further research 
needs to be done on other indications for Herceptin.
	Y-Me was involved with the National Breast Cancer 
Coalition and Genentech in providing information about the 
clinical trials to women with metastatic disease.  Women 
would call Y-Me's national hotline and ask specifically 
about Herceptin and the clinical trials, or they would be 
given information if their circumstance indicated that they 
might be eligible for one of the trials.  If a woman 
expressed interest in the Herceptin study, we would refer 
her to Genentech for eligibility criteria and site location.
	We believe that the following quote from Dr. 
Melody Copely, Director of the Rush Presbyterian St. Luke's 
Medical Center, reflects the promise clinicians see in 
Herceptin that it will make a difference in the lives of 
women with metastatic breast cancer.  She said:  The 
patients who went into this Herceptin trial were in a 
hopeless situation.  I have treated breast cancer patients 
for nearly 20 years.  By the time I treated my third patient 
with Herceptin I knew that a breakthrough was going on.  To 
see some of these patients resurrect themselves from being 
totally bedridden to being fully functional was amazing.  
And, Herceptin didn't cause toxicity.  There was no hair 
loss; no nausea; no vomiting. 
	In the interest of women with metastatic breast 
cancer, Y-Me urges the FDA to approve Genentech's 
application for the drug Herceptin so that it can be made 
available as rapidly as possible for use in the treatment of 
metastatic disease. 
	Thank you.  Are there any questions?
	DR. DUTCHER:  Thank you very much.  Next we will 
read another letter.
	DR. TEMPLETON-SOMERS:  This letter is from Elaine 
Doubrava, from Houston Texas.
	Next Monday, August 24, 1998, will mark my 95th 
trip from my home in Houston, Texas to Birmingham, Alabama.  
These trips started on September 30, 1996 when my name was 
picked from the HER2 lottery to receive the drug on 
compassionate waivers.
	I am a 6-year plus breast cancer survivor.  My 
first metastasis was discovered in January, 1995 and I have 
been in chemotherapy non-stop since then, approximately 43 
months.  My metastases have been in my liver, spine and 
brain.
	In September, 1996, my liver metastasis continued 
to grow in spite of aggressive treatments.  Knowing my 
original tumor was HER2 positive, I called the Birmingham 
location and asked to have my name put in the lottery for 
the next drawing.  I was very fortunate as my name was 
selected on the first drawing.  My first HER2 treatment was 
October 7, 1996.
	My first 12-week checkup was right before 
Christmas, December 23, 1996.  What a gift!  My liver 
lesions had shrunk approximately 73 percent.  I was elated 
and so very grateful to Genentech and Kirklin Clinic. 
	I realize a cure for my cancer is yet to be found, 
but Herceptin has certainly afforded me two years of quality 
time I know I would not have had otherwise.  No side effects 
from Herceptin whatsoever.
	I have gone through about 8 different chemotherapy 
treatments utilizing 14 different drugs.  I have been 
through high dose chemo.  After total head radiation, I will 
probably never have a full head of hair again, but that's 
okay, I am alive and I attribute my being alive to 
Herceptin.
	I would like to urge the FDA to approve this drug 
so that it may get to the many women in need of it as 
quickly as possible. 
	I was informed of my first recurrence on my 49th 
birthday.  I never thought I would see age 50.  Now, thanks 
to Genentech and Herceptin I may see birthday number 53.  
Elaine Doubrava, Houston, Texas.
	DR. DUTCHER:  Our next speaker is Miss Marilyn 
McGregor.
	MS. MCGREGOR:  Thank you.  My name is Marilyn 
McGregor.  I am the Administrative Director of the Cancer 
Support Community located in San Francisco.  I have no 
financial interest in Genentech.  The company did not pay 
for my trip, nor did they read or edit my remarks.  The 
Cancer Support Community received $3000 in 1996 for 
community support, and a $1000 donation as an honorarium for 
our board members. 
	I want to say at the outset that I urge approval 
of Herceptin and immediate marketing of the drug.  It is a 
great breakthrough and a great chance to extend life for 
women with refractory cancer.  However, women should not 
have to wait until November for access to this important new 
therapy.  We have waited too long already.
	Four years ago this December I, along with two 
other breast cancer activists, Grace Buflavin and Linda 
Reyes, under the sponsorship of the Breast Cancer Committee 
of ACTUP, Golden Gate, held a demonstration of civil 
disobedience at Genentech's South San Francisco 
headquarters.  Through allies such as ACTUP and Project 
Inform and other AIDS advocacy groups, and over a long 
series of meetings we were eventually able to negotiate 
several major advances for women with breast cancer.
	The first was a crossover protocol so that women 
who showed disease progression were able to get Herceptin.  
This is a common design in HIV AIDS trials but is not common 
in breast cancer trials.
	Another advance was Genentech's eventual agreement 
to have an expanded access, compassionate access protocol 
for those who did not meet the criteria for the various 
trials.  Although modest in number, 200 women over 2 years, 
the first expanded access trial protocol was a pioneering 
achievement and the first in the history of breast cancer 
trials, and Genentech is to be commended for this pioneering 
effort. 
	Of course, the National Cancer Institute has 
always had a variety of compassionate access mechanisms but 
comparatively few people know of them and utilize these 
mechanisms.  Yet, compassionate access, expanded access is 
commonplace in HIV AIDS drug development. 
	We were pleased that Genentech and NCI finally 
developed an open-label Herceptin trial for 500 women.  But 
this trial was slow to start up and slow to receive IRB 
approval in the 40 sites.  We had expected the start-up in 
January-February, but people only began to become enrolled, 
and the IRBs approved, in June and July.  However, at this 
point women still have to enter a lottery in the 
NCI-Genentech's trial as there is reportedly a limited 
supply of drug. 
	In our meetings with Genentech over the past nine 
months, the supply issue was reportedly the reason for the 
continued lottery.  Of course, if a company does not a 
schedule production run there will be insufficient drug.  It 
appears now that the supply of Herceptin is no longer 
limited. 
	We have learned that additional Herceptin trials 
are under way at Memorial Sloan Kettering, M.D. Anderson and 
in Florida comparing responsive women who overexpress HER2 
with women who do not overexpress the protein.  Therefore, 
it is time to end the lottery.  All women in the applicant 
pool should have drug made available to them now.  I repeat 
-- now. 
	The trial will accrue its full number of 
applicants and many hundreds of women will have the 
opportunity to possibly extend their lives.  If this was an 
AIDS drug that showed the kind of effectiveness that 
Herceptin has shown, even with the cardiotoxicity, it would 
have had really fast track approval.  Six months is the 
maximum time for FDA fast track approval.  There is no 
minimum amount of time. 
	The major labeling issue for cardiotoxicity is in 
Herceptin.  Considering that Herceptin does not have the 
many other known toxicities of commonplace chemotherapies, 
this major labeling issue could be resolved in brief focused 
sessions so that the drug could be ready for marketing in 
two weeks instead of two months. 
	I ask that all those concerned about the lottery 
issue and immediate access contact the FDA or their 
congressional representatives.  The lottery women need 
Herceptin now. 
	Thank you.
	DR. DUTCHER:  Thank you.  We have one more letter. 
	DR. TEMPLETON-SOMERS:  This letter is from Dr. 
Philip Wyatt, who is Chief of the Department of Genetics at 
the North York General Hospital in Ontario, Canada. 
	Thank you very much for allowing me to write a 
letter to be entered into the record regarding the 
consideration of Herceptin as a possible approved drug.
	It would appear from the preliminary research 
which is available, the use of the HER2 antibody Herceptin 
may potentially provide great value in the treatment of 
certain forms of breast cancer.
	Ours is an institution that is involved in seeing 
a number of women who do have early cases of breast cancer 
and cases which are advanced and have failed all therapies.
	We have been investigating the improved diagnostic 
capacities of breast cancer and have, as many others, found 
that the laboratory testing for HER2 overexpression is quite 
reliable.  We specifically use the Vysis-related probes by 
fluorescent in situ hybridization and we are finding on a 
double-blinded study that approximately 20 percent of 
patients who present with breast cancer are overexpressors 
of the HER2 gene.
	It would appear that this is a situation where the 
technology is advancing over the means by which promising 
therapies may be introduced.  As a result, I am writing the 
FDA in support of a rapid evaluation and availability for 
Herceptin.
	The dilemma we personally find ourselves in is 
that we now can accurately and reliably diagnose biological 
activity which is different in some women who have breast 
cancer, yet a potential therapy targeted specifically 
against the biological activity is not available.  It 
creates the dilemma of perhaps not making the test even 
available to women who request it or pointing out that, yes, 
their test is positive but there are no available therapies 
which are accepted.
	I think I truly do appreciate the dilemmas that go 
on in making sure that appropriate clinical trials are 
addressed, drugs are appropriately brought to the worldwide 
health care system in a responsible and well-thought out 
fashion, and also the complex nature of global health care 
industries. 
	One possible solution to deal with these new 
category of targeted biologicals against gene activities and 
the like would be a mandated linkage of the companies 
providing diagnostic laboratory testing, either approved lab 
testing services or biotech companies, and the 
pharmaceutical companies producing the Herceptin.  A pool of 
resources could be created from the sale of Herceptin or the 
lab test, in essence, an FDA tax, and the pool of resources 
would be used specifically and solely for creating a 
database and a large worldwide clinical trial investigating 
the response of HER2 antibody Herceptin for those women who 
are confirmed to be either HER2 negative or HER2 positive 
through accredited lab services. 
	I appreciate the opportunity of at least 
expressing some of the front-line concerns regarding the 
changes which are going on in the treatment of breast cancer 
and do look forward to receiving a copy of the deliberations 
of your meetings.  Sincerely, Philip Wyatt, M.D., Ph.D., 
Chief, Department of Genetics at North York General 
Hospital.
	DR. DUTCHER:  While the sponsor is setting up the 
slides, we have Dr. Julie Goldstein who is going to provide 
an overview. 
Introduction of the Issues
	DR. GOLDSTEIN:  Good afternoon. 
	[Slide]
	I am Julia Goldstein, chair of the CBER committee 
and product reviewer of the biological license application 
for Herceptin.  The Center for Biologics has been reviewing 
the Herceptin license application submitted by Genentech 
which is indicated for treatment of patients with metastatic 
breast cancers whose tumors overexpress the HER2 receptor.  
In parallel, the Center for Devices and Radiological Health 
has been reviewing the immunohistochemistry kit, submitted 
by DAKO Corporation that, should accompany this product.  
The indication of the immunohistochemistry kit is to 
determine patient eligibility for treatment.  The 
immunohistochemistry kit will be presented to an advisory 
committee next Friday, September 4.
	[Slide]
	I would like first to acknowledge the members of 
the CBER committee:  Keith Weber, regulatory coordinator; 
Susan Jerian, clinical reviewer, and you will hear from her 
at a later time; Genevieve Schechter, clinical reviewer; 
Teresa Neeman, statistical reviewer; Dave Green, pharm-tox 
reviewer; Walter Lange and Lloyd Johnson, establishment 
reviewers; Debra Bower, bioresearch monitoring coordinator; 
and Kurt Stromberg, product consultant. 
	Breast cancer is one of the most common 
malignancies in women.  It accounts for a third of the 
female cancers in the U.S.A. and remains a serious health 
care problem.  Thirty percent of the primary breast cancers 
overexpress the HER2 receptor.
	[Slide]
	During my presentation I would like to briefly 
describe the following four issues:  First, the biology of 
the HER2 receptor.  The second is what is the 
pathobiological significance associated with the HER2 
overexpression.  What is the clinical relevance associated 
with HER2 overexpression, and finally, what is Herceptin and 
how does it work.
	[Slide]
	HER2 belongs to the ErbB family.  This family is 
constituted by four receptors.  All of them share extensive 
sequence homology, which suggests similar mechanisms of 
activation and signaling. 
	On the right-hand side of the slide are some of 
the ligands known to bind to each one of these receptors.  I 
want to point out that no ligand has yet been characterized 
that binds the HER2 receptor. 
	The current view is that HER2 is the preferred 
dimer partner for the other three members and functions as a 
co-receptor, amplifying the signals transduced by the other 
three. 
	[Slide]
	HER2 is a membrane glycoprotein of 185 kilo 
daltons.  It consists of an extracellular domain, rich in 
cysteine -- presented in pink, and this will be so 
throughout the presentation -- a single transmembrane domain 
and an intracellular domain with tyrosine kinase activity. 
	HER2 expression has been extensively studied in 
adult and fetal tissues.  Its expression has been shown on 
epithelial cells derived from three germ layers, in 
particular, the gastrointestinal, respiratory, urogenic and 
skin, breast and placenta.  It has also been shown to be 
expressed in neurons, Schwann cells and glia and muscle 
cells. 
	The study collaborators have shown that HER2 plays 
a crucial role in cardiac and central nervous system 
embryonic development.  The mice that carry the null allele 
die at embryonic age of 11 days due to a dysfunction 
associated with a lack of cardiac trabeculation.  These mice 
also had altered development of the neural crest-derived 
sensory ganglia and motor nerves.  These results indicated 
that HER2 plays a role in mesenchymal-epithelial 
communications.
	[Slide]
	What is the physiological role of HER2?  HER2 
participates in an interactive network of receptor-receptor 
interactions with a high degree of pathway 
intercommunications.  These interactions regulate cell fate, 
growth and proliferation. 
	HER2 acts in a cooperative manner with other ErbB 
proteins as a shared, low affinity co-receptor for multiple 
stroma-derived growth factors.  Upon ligand binding to each 
one of these receptors -- and I want to emphasize here, 
again, that HER2 is in pink -- the tyrosine kinase 
phosphorylates.  The complex of ligand-receptor now 
heterodimerizes with HER2 which transphosphorylates.  The 
tyrosine kinase now becomes docking sites for multiple 
substrate and docking proteins, and these culminate in MAP 
kinase activation and, finally, in the regulation of 
proliferation, cell survival or differentiation.  In other 
words, this oncoprotein acts as a shared signaling subunit 
of primary growth factor receptors, prolonging and enhancing 
signal transduction specifically through MAP kinase. 
	[Slide]
	What is the pathobiological significance 
associated with HER2 overexpression?
	[Slide]
	In vitro studies have shown that HER2 
overexpression is an important component of neoplastic 
transformation.  Tumors that overexpress HER2 lead to 
constitutive activation of the receptor, and this translates 
into an increased proliferation rate and increased 
resistance to TNF-alpha, decreased expression of adhesion 
molecules, in particular E cadherines and alpha-2 integrins, 
which have been demonstrated to be associated with 
metastasis progression and development, and increased 
vascular endothelial growth factor secretion which supports 
new vascular formation. 
	[Slide]
	What is the clinical relevance associated with 
HER2 overexpression? 
	[Slide]
	Retrospective analyses of clinical data have 
demonstrated that HER2 overexpression is a negative 
prognostic indicator.  Patients whose tumors overexpress 
HER2 have shorter disease-free interval and a shorter 
overall survival.  HER2 has been seen as predictive of 
aggressive disease, regardless of disease stage or node 
status.  These tumors are more invasive.  They have a higher 
incidence of metastasis, and they are more resistant to 
chemotherapy.
	[Slide]
	Finally, what is Herceptin and how does it work?
	[Slide]
	Herceptin is a recombinant humanized murine 
monoclonal antibody in which the complement-determining 
regions, derived from the 4D5 antibody, have been grafted 
into the human backbone of IgG1.  It contains 6 percent of 
murine residues, and it binds with high affinity to the 
extracellular domain of the HER2 receptor.  	Herceptin 
is produced at large scale in CHO cells and is purified by 
standard chromatographic procedures.
	[Slide]
	In vitro studies have demonstrated that Herceptin 
exerts its effect mainly by two arms.  This slide sows the 
biochemical effects and the next slide will show the 
immunological arm of the response. 
	The biochemical effects are pictured inside the 
circle, and are due to the antibody binding to the HER2 
receptor.  In vitro studies demonstrated that Herceptin 
mediates receptor down-modulation, and also 
heterodimerization blockade.  Both of them lead to signal 
transduction blockade.  In addition, Herceptin has a 
cytostatic effect.  In particular, it up-regulates CDK2 
kinase, and also sensitized breast tumor cells to TNF alpha.
	[Slide]
	Immunological response is due to Fc binding to the 
Fc receptor gamma-3 of CD16.  In vitro studies have shown 
that Herceptin mediates antibody dependence and 
cytotoxicity, and it is postulated that the in vivo effect 
would be the recruitment of CD16 bearing cells to the site 
of the tumor.  Other in vitro assays and animal models have 
demonstrated enhancement of chemotherapy-induced 
cytotoxicity.  In particular, Herceptin synergizes with 
cysplatinum and has an additive effect when administered in 
combination with doxorubicin, paclitaxel, methotrexate and 
vinblastine. 
	[Slide]
	In summary, HER2 is expressed at low levels.  It 
functions by forming heterodimers with the other ErbB 
proteins and, therefore, is involved in signal transduction.  
Overexpression leads to constitutive activation of the 
receptor.  Analysis of clinical data has been associated 
with poor prognosis. 
	Herceptin regulates down-modulation of the HER2 
receptor.  It inhibits dimer formation.  It has a cytostatic 
effect, and is able to mediate antibody dependence and 
cytotoxicity. 
	This concludes my presentation. 
	DR. DUTCHER:  Thank you very much.  We have now 
had an overview of the biology and we will now proceed to 
the sponsor's presentation. 
Sponsor Presentation
Introduction and Regulatory History
	[Slide]
	MR. TRASS:  Welcome to the afternoon session of 
the Oncology Drugs Advisory Committee meeting. 
	[Slide]
	For the next hour, Genentech will present the 
results of the clinical program for Herceptin, trastuzumab, 
indicated for the treatment of patients with metastatic 
breast cancer who have tumors that overexpress HER2. 
	[Slide]
	My name is Karl Trass, and I will provide a brief 
regulatory history of the molecule.  Dr. Steve Shak will 
take us through the scientific rationale and clinical 
efficacy, and Dr. Virginia Paton will provide a 
comprehensive safety analysis.  Finally, Dr. Shak will 
return to discuss the benefits and the risks of Herceptin 
treatment. 
	[Slide]
	The human epidermal growth factor receptor 2 gene 
was cloned in 1985, and Genentech has been committed to the 
molecule and to the HER2 program since that time.  Based on 
the murine monoclonal antibody 4D5, we developed a 
recombinant humanized monoclonal antibody, and initiated 
Phase 1 clinical trials in 1992, and followed with Phase 2 
the next year.  Based on these encouraging results in which 
we demonstrated activity and safety, we met with the agency 
to discuss the clinical program and the manufacturing plans 
for Herceptin.  At that time, we obtained agreement on the 
Phase 3 protocols and initiated the Phase 3 program the 
following year.  They were only completed in 1997, and in 
1998, in March of this year, Herceptin was designated a 
fast-track biologic.  At the same time, we began a BLA 
submission with the agency and completed the application on 
May 1 of this year. 
	[Slide]
	Genentech is seeking approval based on two pivotal 
studies.  The first study, Herceptin in combination with 
chemotherapy in first-line metastatic disease, enrolled 469 
women.  This trial was originally designed as a 
placebo-controlled trial. 
	Accrual to the protocol was slow, and we amended 
the protocol to allow women who had received prior 
anthracyclines in the adjuvant setting to enroll and receive 
paclitaxel as a therapeutic option. 
	Early in 1996, accrual was still slow.  We began 
discussions with the agency to amend the protocol to an 
open-label, randomized, controlled study.  However, the 
primary endpoint of time to disease progression did not 
change. 
	Amendment 2, discontinue for placebo, broaden the 
eligibility requirements, and simplify study procedure to 
include the discontinuation of cardiac monitoring.  This 
amendment did facilitate enrollment.  Early in 1997, we 
received 4 unexpected cases of cardiac dysfunction.  At that 
time, we alerted investigators, agencies worldwide and, most 
importantly, the patients of these unexpected events.  The 
third and final amendment reinstituted noninvasive cardiac 
monitoring. 
	[Slide]
	The second pivotal study, Herceptin as a single 
agent in relapsed metastatic disease, enrolled 222 women.  
This protocol was amended twice.  First at the suggestion of 
the FDA, we moved a co-primary endpoint of time to disease 
progression to a secondary endpoint, but the primary 
endpoint of response rate did not change. 
	The second amendment allowed women with one prior 
chemotherapy regimen to enroll, and also broadened the 
therapeutic options if patients progressed while on study. 
	[Slide]
	That was a very brief regulatory history.  For the 
rest of the afternoon, Genentech scientists and advisors 
will be here to answer any questions you may have.  At this 
time, I will turn it over to Dr. Shak and he will take us 
through the scientific rationale and the clinical efficacy.
Scientific Rationale and Clinical Efficacy
	DR. SHAK:  Hello, good afternoon. 
	[Slide]
	My name is Steven Shak, and I appreciate the 
opportunity today to present the results of the Herceptin 
studies. 
	[Slide]
	In the last decade, a number of exciting and 
important breakthroughs have occurred with regard to an 
increased understanding of the molecular mechanisms that 
cause cancer.  Specific defined DNA alterations, some 
inherited and some acquired, have been elucidated.  In 
addition, we have defined precise molecular mechanisms by 
which the growth of cells is regulated.  The Herceptin 
program arose out of the discovery of a specific genetic 
alteration in breast cancer.
	[Slide]
	In 25-30 percent of women with breast cancer there 
is amplification of the HER2 oncogene which is associated 
with overexpression of the HER2 protein, here shown by 
immunohistochemistry.  Most importantly, it was shown that 
amplification and overexpression leads to poor prognosis and 
shortened survival.  This is not just a marker of bad 
prognosis but, in fact, there is clear evidence that 
suggests that HER2 amplification overexpression is causally 
related to the cancer progression. 
	For example, studies have been performed where the 
rodent homolog of HER2 is introduced into a mouse, creating 
a transgenic mouse and, as shown here, the HER2 transgenic 
females developed breast tumors at a high incidence.  It 
was, therefore, on the basis of this data that HER2 was 
specifically targeted. 
	[Slide]
	Herceptin is a humanized anti-HER2 monoclonal 
antibody, highly specific and binding with high affinity to 
breast cancer cells that overexpress HER2.  Genetic 
engineering created a molecule, as shown here in grey, which 
is 95 percent human.  Murine residues are shown in yellow.  
It was intended by the humanization to decrease the 
potential for immunogenicity and to increase the potential 
for increasing the recruitment of immune effector 
mechanisms.
	[Slide]
	Since Dr. Goldstein did such a very nice job, I 
will briefly summarize the preclinical data.  With regard to 
efficacy, Herceptin is active in cell culture.  Most 
importantly, it directly inhibits HER2 overexpressing breast 
cancer cells at a concentration of 1-10 mcg/ml.
	[Slide]
	As shown on this slide, in experiments performed 
in the murine xenograft model Herceptin inhibits tumor 
growth in a dose-dependent fashion, as shown here at 3, 10, 
30 and 100 mg/kg doses compared to no effect of the control 
immunoglobulin.  In these studies, serum assays identified 
that the target trough serum concentration for activity was 
10-20 mcg/ml, concentrations that were readily achieved by 
the human clinical dose. 
	[Slide]
	Finally, studies were performed with Herceptin in 
the murine xenograft model to evaluate its activity in 
combination with chemotherapy.  Here are doxorubicin and 
paclitaxel.  With both agents it was shown that the 
combination of Herceptin plus chemotherapy, shown in blue, 
had the greatest activity, more activity than the antibody 
alone or chemotherapy.  It was on the basis of these studies 
that the pivotal clinical trials were designed. 
	[Slide]
	Finally, with regard to safety, an extensive 
series of studies was performed.  Studies were performed in 
animals, examining Herceptin doses at a concentration up to 
12.5 times the human clinical dose.  It was well tolerated 
at all doses.  There was no effect on heart rate or ECG.  No 
anaphylaxis was observed.  And, as expected, clearance from 
the serum was slow, with a half-life of 5-10 days.  Tissue 
binding studies showed that Herceptin recognizes epithelial 
cells from a variety of tissues but no detectable binding 
was shown with cardiac or neural tissues. 
	[Slide]
	In summary, the preclinical studies demonstrated 
activity and an excellent preclinical safety profile. 
	[Slide]
	I would now like to turn to the clinical program 
and then to summarize the results with regard to clinical 
efficacy.
	A series of 10 clinical trials were performed with 
Herceptin, 5 Phase 1 and Phase 2 studies were performed with 
Herceptin as a single agent and in combination with 
chemotherapy which identified that Herceptin was active, 
which defined that it was well tolerated, and which 
identified the dose and schedule that was used in the 
pivotal clinical trials. 
	The pivotal clinical trials are, first, the 
comparative study of Herceptin plus chemotherapy versus 
chemotherapy alone, a randomized, controlled study in women 
with no prior chemotherapy for metastatic disease.  This 
study, H0648g, enrolled 469 women. 
	The second study, a study of single-agent 
Herceptin in more advanced disease, enrolled patients who 
had relapsed following 1 or 2 prior regimens of chemotherapy 
for metastatic disease.  This study, H0649g, enrolled 222 
women.
	There are 3 other ongoing studies, first, an 
open-label extension study for women with disease 
progression in a comparative trial.  Second, a single-agent 
study in women with no prior chemotherapy for metastatic 
disease.  As described previously, we have had an expanded 
access program since the beginning of 1996. 
	At this time, I would very much like to 
acknowledge a number of key contributors:  First, the 
investigators and their staff that participated and 
performed these trials; second, the breast cancer patient 
advocates that advised us, that served on our steering 
committee and that served on the data safety monitoring 
committee; and finally, and most importantly, the patients 
and women who volunteered for this clinical trial.  In 
addition, we have had extensive and useful advice from the 
FDA, both the Division of Biologics as well as the Office of 
Women's Health and the Cancer Liaison. 
	[Slide]
	There are two features of the pivotal trials which 
I would like to discuss specifically because they were key 
and important to the conduct of the study.  First, as Karl 
mentioned in the introduction, the comparative trial was 
amended to remove the placebo. 
	To maintain and have the highest rigor and 
objectivity with regard to assessment of the primary and 
secondary disease progression and tumor response endpoints 
in this study, we established an independent response 
evaluation committee which reviewed efficacy on an ongoing 
basis during the course of the clinical trial.  Reading 
teams were composed of radiologists and oncologists.  Only 
objective tumor data -- films, photographs and physical exam 
measurements -- were reviewed, and the response evaluation 
committee remained blinded.  They had no knowledge as to 
whether the patient was on the comparative trial or on the 
single-agent study, and in all cases they remained blinded 
to treatment assignment.
	Finally, disease progression determined by the 
response evaluation committee was required in order to get 
entry into the open-label extension so that no patients on 
the control arm could get access to Herceptin without 
documented disease. 
	[Slide]
	The second key feature of this study that I would 
like to refer to relates to HER2 testing.  At the time of 
the initiation of the pivotal studies there was no approved 
diagnostic for measuring levels of HER2 overexpression.  To 
provide rigor and standardization, therefore, we established 
a central core laboratory which used a standardized 
immunohistochemistry assay.  And, 2+ or 3+ overexpression 
was required for study entry. 
	As described by Dr. Goldstein, subsequently we 
have collaborated with a diagnostics company to develop a 
commercial immunohistochemistry kit which was studied for 
its concordance with the clinical trial assay.  This kit 
will be reviewed on Friday, at a diagnostics advisory 
committee meeting. 
	[Slide]
	With regard to the single-agent study, H0649g, 
this was a single-arm, open-label study.  Women were treated 
with Herceptin, with a 4 mg/kg loading dose and then 2 mg/kg 
IV weekly.  Efficacy was assessed at regularly scheduled 
intervals and, as I mentioned previously, tumor response was 
determined by the response evaluation committee.
	[Slide]
	Shown here are the demographics of the women 
enrolled in this clinical trial.  As might be expected for 
patients, all of whom had overexpression of HER2, there is 
evidence for aggressive disease and extensive prior 
treatment.  More than half the patients, 55 percent, were ER 
negative.  A third of patients, 36 percent, had disease at 3 
or more metastatic sites, and 70 percent had disease in the 
liver or lung.
	[Slide]
	As required per protocol, all patients had at 
least 1 prior chemotherapy regimen for metastatic disease, 
and 32 percent had 1, and 68 percent had 2 prior regimens; 
68 percent had prior adjuvant chemotherapy and 26 percent 
had prior transplant; 94 percent had been treated with 
anthracyclines and 67 percent had been treated with taxanes 
previously. 
	[Slide]
	The prospectively defined endpoints of this 
clinical trial are listed here.  The endpoints were assessed 
and the data will be presented today by an intent-to-treat 
approach.  The primary endpoint of this study was overall 
response rate as determined by the REC.  The secondary 
endpoints included duration of response, time to 
progression, survival and quality of life.
	[Slide]
	Shown here are the results for the primary 
prospectively defined endpoint of the study.  The overall 
response rate as determined by the REC was 15 percent.  
There were 8 complete responses and 26 partial responses. 
	[Slide]
	The duration of response is plotted here from 
months or time from the initial response.  It is notable 
that in the responders the median duration of response was 
9.1 months.
	[Slide]
	Time to progression was assessed, as shown on this 
slide.  The median time to progression was 3 months and 22 
percent of patients were free of progression at 6 months.
	[Slide]
	Finally, shown here is survival from time of first 
treatment.  The median survival in this patient population 
was 13 months. 
	[Slide]
	In examining the efficacy in this study, we 
assessed subgroups in order to examine the consistency of 
clinical benefit.  The confidence intervals for all 
subgroups examined overlapped the overall response rate of 
15 percent. 
	[Slide]
	In addition to the results of this clinical trial, 
H0649g, that we have just reviewed, we also have data from 2 
other single-agent studies.  The Phase 2 study, H0551g, 
showed a response rate of 11 percent.  In a preliminary 
analysis of the results of the single-agent study in women 
with no prior chemotherapy for metastatic disease the 
response rate is 24 percent. 
	[Slide]
	In summary, therefore, Herceptin as a single agent 
is active and induces objective, durable tumor responses.  
There is consistent evidence of tumor response in subgroups.
	[Slide]
	We will now turn to the comparative trial.  This 
study enrolled 469 women.  Women were eligible if they had 
metastatic breast cancer, HER2 overexpression, no prior 
chemotherapy for metastatic disease, and all women had to 
have measurable disease. 
	A key feature of this study is shown on this 
slide.  Patients were stratified to chemotherapy based on 
their history of chemotherapy in the adjuvant setting.  
Women with no prior anthracyclines in the adjuvant setting 
were randomized to Herceptin plus anthracycline 
cyclophosphamide, or AC, or AC alone.  Women who had prior 
anthracycline in the adjuvant setting were randomized to 
Herceptin plus paclitaxel or paclitaxel alone.  We might 
expect, and in fact did see, that the AC stratum was a 
population different from the paclitaxel stratum.
	[Slide]
	Treatment in this study was protocol specified.  
Herceptin was administered at the same dose and schedule 
used in the previous study.  Chemotherapy was also protocol 
specified.  AC or doxorubicin or epirubicin plus 
cyclophosphamide was administered at a standard dose and 
schedule.  Paclitaxel was also administered at a standard 
dose and schedule.  To provide data relevant to the 
real-world of oncology practice, chemotherapy could be 
continued for more than 6 cycles at the discretion of the 
investigator. 
	[Slide]
	We will now examine the demographics of the 
patients enrolled in this clinical trial.  The data is shown 
on the next 2 slides, and I am going to go through it slowly 
and focus on 3 major points.  First, the population as a 
whole; second, the balance within chemotherapy stratum; and, 
third, the balance between chemotherapy stratum. 
	With regard to the patients enrolled in this 
study, as was the case with the single-agent study, in women 
who were all HER2 positive we saw evidence of aggressive 
disease.  A third of the women had a Karnofsky performance 
status of 80 percent or less.  Again, a third had metastatic 
disease at 3 or more sites.  Half were ER negative and a 
high percentage of the women at primary diagnosis had 4 or 
more positive lymph nodes.
	With regard to balance within chemotherapy strata, 
randomization was successful.  In other words, the 
population of patients in the Herceptin plus AC stratum was 
comparable to that in the AC.  The group of patients in the 
Herceptin plus paclitaxel arm were, again, similar to those 
in the paclitaxel treatment arm.  The only imbalance on this 
slide that achieves statistical significance is noted with 
the asterisk here.  There was a higher percentage of women 
with a lower performance status in the paclitaxel alone 
group, an imbalance in favor of Herceptin.
	[Slide]
	On this slide is shown prior treatment in the 
patients enrolled in this study.  There was, again, only one 
imbalance within chemotherapy strata, shown here.  In this 
case, more patients in the Herceptin plus AC stratum 
received prior adjuvant chemotherapy, 57 percent versus 37 
percent, in this case an imbalance in favor of the control 
group. 
	Finally, with regard to the demographics, we do, 
in fact, see that the paclitaxel patients are different than 
the AC patients.  They had more adjuvant chemotherapy and 
they had a higher percentage of prior transplants.  With 
regard to these imbalances, we incorporated a correction for 
these imbalances in the statistical analyses that were 
performed with regard to efficacy.
	[Slide]
	The endpoints of this study are shown here.  The 
primary endpoint is time to disease progression as 
determined by the response evaluation committee.  The 
secondary endpoints included overall response rate, duration 
of response, time to treatment failure, 1-year survival and 
quality of life.
	[Slide]
	This is a Kaplan-Meier plot showing the results of 
the primary, prospectively defined endpoint of time to 
disease progression.  The percentage of patients free of 
disease progression or death is plotted as a time from 
randomization.  Shown in yellow are the results for the 
treatment group of Herceptin plus chemotherapy.  Shown in 
green are the results with chemotherapy alone.  Herceptin 
significantly increases the time to disease progression.  
The median time to disease progression with chemotherapy 
alone was 4.6 months versus 7.6 months with Herceptin plus 
chemotherapy. 
	As can be seen, at 12 months a greater percentage 
of women are free of progression when treated with Herceptin 
plus chemotherapy, 28 percent versus 9 percent with 
treatment with chemotherapy alone.  The overall difference 
with regard to time to disease progression was statistically 
significantly different, with a p value of 0.0001. 
	[Slide]
	The results of the analysis for time to disease 
progression broken out by chemotherapy strata are shown on 
this slide.  For the AC strata we observed a significant 
increase in time to disease progression.  A median of 6.1 
months increased to 8.1 months with Herceptin plus AC.  The 
paclitaxel strata showed a median time to progression of 3 
months with paclitaxel alone versus 6.9 months with 
Herceptin plus paclitaxel.  As you can see, the magnitude of 
the treatment effect is greater with paclitaxel. 
	These results were done with data that was 
submitted in our BLA.  As noted in the FDA briefing book, we 
have since, at their suggestion, performed 68 additional 
reviews of patients in this clinical trial.  That additional 
information shows high concordance, actually, between the 
investigator and the REC.  You have been handed a summary 
that outlines the updated data analysis for both time to 
progression as well as the other efficacy endpoints.  Those 
results are consistent with the data which is being 
presented here. 
	[Slide]
	The overall response rate was also significantly 
increased by Herceptin.  The overall response rate was 32 
percent with chemotherapy alone and 49 percent with 
Herceptin plus chemotherapy. 
	[Slide]
	We saw also increases in overall response rate 
with AC and with paclitaxel.  With AC alone, 43 percent; 
Herceptin plus AC, 52 percent; with paclitaxel alone, 16 
percent; and with Herceptin plus paclitaxel, 42 percent. 
	[Slide]
	We also examined the duration of response.  The 
median duration of response was 6.5 months with AC alone 
compared to 9.1 months with Herceptin plus AC.  The median 
duration of response was 4.4 months versus 11 months with 
Herceptin plus paclitaxel.  Thus, not only did Herceptin 
increase the percentage of women who had a tumor response, 
but in those women who had a response it significantly 
increased the duration of response. 
	[Slide]
	Time to treatment failure was prespecified and 
defined as time to disease progression, death, 
discontinuation of study or discontinuation of Herceptin for 
any reason, or the initiation of new anti-tumor therapy.  
Herceptin significantly increased the time to treatment 
failure when used both in combination with AC and in 
combination with paclitaxel. 
	[Slide]
	Quality of life in this study was assessed using a 
validated EORTC questionnaire.  Overall, there was no 
significant difference between groups. 
	[Slide]
	However, trends for maintained quality of life as 
shown on this slide were seen in patients treated with 
Herceptin plus chemotherapy.  Shown here is the quality of 
life domain plotted as change from baseline at week 8, week 
20 and week 32.  At week 8, during chemotherapy in both 
groups there is a decline in quality of life.  At week 20 
and at week 32, there is a trend for maintained quality of 
life with Herceptin plus chemotherapy compared to a 
persistent decrease with chemotherapy alone. 
	[Slide]
	Finally, 1-year survival was an important 
prespecified secondary endpoint.  Survival data, as of March 
1998, is available in 99 percent or more of the patients.  
The survival in the chemotherapy alone group at 1 year was 
67 percent and was increased with Herceptin treatment to 78 
percent, an increase which was statistically significant 
with a p of 0.008. 
	[Slide]
	In addition, we examined the Kaplan-Meier curve of 
overall survival for the data available as of March, 1998.  
The Kaplan-Meier curve, shown here, probability alive 
plotted as time from randomization in months shows, in 
yellow, with Herceptin plus chemotherapy the early survival 
advantage.  A difference in survival is observed as early as 
6 months after randomization.  We are cautious in 
interpreting this part of the Kaplan-Meier curve at this 
time. 
	[Slide]
	On this slide is shown the percentage of patients 
with follow-up at each point in time following 
randomization.  We have a lot of data with regard to the 
early time points of follow-up.  As much as 81 percent of 
patients have reached a survival follow-up time of 15 
months, but only about 40 percent have reached a survival 
follow-up time of 25-30 months.  We clearly look forward to 
updating the survival data with continued follow-up in order 
to better define survival in this region. 
	[Slide]
	In addition to the immaturity of the data at this 
point in time, we also need to note the crossover that was 
allowed per protocol.  With REC documented disease 
progression, women could get Herceptin in the open-label 
extension study. 
	As you can see, even at some of the earlier time 
points, at 10 months for example, 25 percent of the patients 
in the chemotherapy alone group entered the open-label 
extension study and were receiving Herceptin.  At later time 
points almost 60 percent of the control arm patients had 
received Herceptin.  This crossover, therefore, confounds 
our ability to assess overall survival, and makes this early 
difference, I think, even more notable. 
	[Slide]
	With regard to survival, we also examined survival 
at 1 year in both the AC stratum and in the paclitaxel 
stratum.  With AC alone, survival at 1 year was 72 percent 
and increased to 83 percent with the addition of Herceptin.  
With paclitaxel alone, the survival at 1 year was 60 percent 
and increased to 72 percent with the addition of Herceptin.
	[Slide]
	Finally, as we did in the single-arm study, we 
also performed subgroup analysis in order to assess the 
overall benefit.  I will take you through the subgroup 
analysis that we performed in the next 3 slides.  Overall, 
as you will see, consistency was demonstrated.  However, 
testing did indicate a significant interaction between 
treatment group and the level of HER2 overexpression.
	[Slide]
	Let me take you through this slide slowly, 
focusing first on this part of the slide.  Plotted here for 
the primary endpoint of time to disease progression is the 
relative risk of disease progression where the solid white 
line at 1.0 would indicate equivalent risk of disease 
progression between the Herceptin plus chemotherapy group 
and the chemotherapy alone group.  A risk reduction of less 
than 1, as shown here for the overall population, would 
indicate that the combination of Herceptin plus chemotherapy 
is better.  A risk ratio of greater than 1 would indicate 
that the combination of Herceptin plus chemotherapy is 
worse. 
	Shown here for the overall population and then for 
these patient subgroups that were examined was the point 
estimate of the risk ratio of time to disease progression, 
with the lines indicating the 95 percent confidence 
intervals.  Finally, the size of the squares is proportional 
to number of patients in the subgroup. 
	The data here indicate that with regard to the 
subgroups of age, race, Karnofsky score, disease-free 
interval and number of metastatic sites at study entry, we 
see that the point estimates for the reduction in the risk 
of disease progression indicate that Herceptin plus 
chemotherapy is better.  In all cases, the confidence 
intervals overlap the point estimate of the overall result.
	[Slide]
	 On this slide are shown additional subgroups.  We 
noted that testing indicated an interaction with the level 
of HER2 overexpression.  This interaction can be seen right 
here.  With HER2 overexpression at the 2+ level the risk of 
disease progression in patients treated with Herceptin plus 
chemotherapy is a risk ratio of 0.8 compared to 0.4 for 
those enrolled with 3+ overexpression.  As you can see, 
fewer patients, as indicated by the size of the square, had 
a 2+ level of overexpression, and the confidence intervals 
are broader.  Note, however, although there is a lesser 
magnitude of benefit, these results do not indicate a lack 
of benefit or that these patients did worse. 
	[Slide]
	Finally, with regard to the last group of 
subgroups, we again see a consistent evidence of treatment 
benefit with regard to time to disease progression for all 
these subgroups that were examined.  In no case did the 
results indicate that Herceptin plus chemotherapy was worse.
	[Slide]
	In summary then with regard to the efficacy in 
this randomized, controlled trial, the addition of Herceptin 
to chemotherapy significantly increases the clinical 
benefit.  Time to disease progression is increased.  
Response rate and duration is increased.  Time to treatment 
failure is increased, and survival at 1 year is increased. 
	[Slide]
	We will now turn to a discussion of clinical 
safety by Dr. Paton.
Clinical Safety
	DR. PATON:  Thank you, Dr. Shak.  Good afternoon.
	[Slide]
	The safety of Herceptin will be described in two 
settings this afternoon, first as a single agent using data 
from the pivotal H0649g study and then, secondly, in 
combination with chemotherapy using data for the pivotal 
H0648g study. 
	As Karl alluded to in his introduction, we 
identified a cardiac safety concern, and I will close my 
discussion of the safety of Herceptin this afternoon with a 
detailed analysis of patients who experienced cardiac 
adverse events.
	[Slide]
	In our safety analysis of Herceptin, all patients 
who received treatment on study were evaluable for safety. 
Safety was assessed in patients who received Herceptin plus 
chemotherapy or Herceptin alone on a weekly basis.  Patients 
who received chemotherapy alone in the pivotal comparative 
study were evaluated every 3 weeks during the period of time 
of therapy administration and then every 2 weeks once 
chemotherapy was stopped.  Patients were evaluated for 
safety until the documentation of disease progression.  As 
Dr. Shak provided you with those details, patients who 
received Herceptin remained on study for a longer period of 
time.  Therefore, patients who received Herceptin were 
evaluated more frequently and for a longer duration compared 
to the patients who received chemotherapy alone. 
	[Slide]
	Safety was assessed using a 3-scale system, mild, 
moderate and severe.  Mild adverse events were those events 
that had no effect on baseline status.  Moderate effects 
were uncomfortable to the patient and had the potential of 
producing impairment.  Severe adverse events were those 
events that caused severe discomfort to those patients. 
	[Slide]
	The safety results that I will present this 
afternoon include adverse events that were observed in 
greater than or equal to 10 percent of the study population; 
serious adverse events that were observed in greater than 
2.5 percent of the study population; and the rate of 
Herceptin discontinuation and the rate of immunogenicity.  
The data presented today are current as of December 31, 
1997. 
	[Slide]
	Beginning with the single agent H0649g study, the 
administration of Herceptin is associated with an 
infusion-related syndrome that is limited in most patients 
to the first infusion.  This graph details those adverse 
events.  The adverse events observed are listed on the Y 
axis and the adverse event rate is listed on the X axis.  
The events that occurred during the first infusion are color 
coded in green and subsequent adverse events are color coded 
in orange.
	Fever and chills were the most common adverse 
events observed with the first dose infusion, along with 
other constitutional symptoms.  These adverse events were 
mostly mild to moderate in severity, and were easily managed 
with the administration of Tylenol or Benadryl, and in some 
patients temporary interruption of the infusion.  These 
adverse events occurred only in 10 patients out of the 213 
patients who received Herceptin in this trial, and only 1 
patient discontinued Herceptin for these adverse events.
	[Slide]
	Here are the adverse events that were observed in 
greater than 10 percent of all patients.  The severity of 
the events are color coded with mild in green, moderate in 
yellow and severe in red.  You will notice two things from 
this graph:  There were no adverse events that were observed 
in greater than 50 percent of the study population, and 
judging by the color coding and the length of the bars, many 
of these adverse events were mostly mild to moderate in 
severity, and severe events were uncommon. 
	[Slide]
	Here are the remaining adverse events that 
occurred in greater than 10 percent of all patients.  Again, 
the adverse events observed were mostly mild to moderate in 
severity as judged by the green and yellow bars, and severe 
adverse events, coded in red, were infrequent. 
	[Slide]
	There was only 1 serious adverse event that was 
reported in greater than 2.5 percent of the patients, and 
that is fever which was observed in 3 percent of patients on 
this trial. 
	[Slide]
	We observed 179 discontinuations of the 213 
patients enrolled to this trial.  This graph details the 
reason for discontinuation by the number of patients who 
discontinued.  The majority of patients discontinued the 
trial for reasons related to disease progression; and 6 
patients discontinued for reasons related to an adverse 
event; 3 patients discontinued for reasons related to 
metastatic breast cancer prior to receiving Herceptin 
therapy on trial; 2 patients discontinued for tuberculosis; 
1 for congestive heart failure; and 1 for anaphylactoid 
reaction with the first dose of Herceptin. 
	[Slide]
	Turning now to the comparative study H0648g, in 
your briefing document we have provided a large table that 
details the adverse events that were observed in greater 
than 10 percent of patients.  What I will present today are 
adverse events that were significantly increased at the 5 
percent level in Herceptin-treated patients, beginning with 
the anthracycline treatment arm. 
	Again, we have color coded our adverse events as 
mild, moderate and severe in green, yellow and red.  The 
adverse events that were observed in the Herceptin treatment 
arm are coded with "H" and are always the first bar in each 
graph. 
	Again, globally you can see that many of these 
adverse events were mild to moderate in severity, and severe 
events were infrequent.  We did observe infusional-related 
symptoms of chills and fever, headache, and pain with the 
first dose of Herceptin.  We also observed cardiovascular 
adverse events of congestive heart failure accompanied by 
cough, dyspnea in Herceptin-treated patients.  We also 
observed some back pain. 
	[Slide]
	We also observed gastrointestinal adverse events 
that were increased in Herceptin-treated patients, nausea, 
vomiting and diarrhea, with some metabolic complications of 
dehydration and hypokalemia.  We also observed an increased 
rate of infection, leukopenia, pharyngitis and insomnia in 
the antrhacycline treatment group. 
	[Slide]
	The serious adverse events that were observed in 
the anthracycline treatment arm included an increase in 
fever, 23 percent in the Herceptin plus anthracycline arm 
compared to 16 percent in the anthracycline alone arm.  
However, the rate of sepsis was roughly balanced across the 
treatment groups, and we also observed pneumonia.  We did 
observe serious events of congestive heart failure, and 
cardiomyopathy increased in the Herceptin plus treatment 
group compared to the control arm.
	[Slide]
	In patients who received Herceptin plus AC, we 
observed 111 discontinuations of the 143 patients who were 
enrolled and treated in this arm.  The majority of patients 
discontinued for reasons related to disease progression, 
however, 20 patients discontinued Herceptin for an adverse 
event.  The majority of these adverse events were 
cardiovascular in nature. 
	[Slide]
	Turning now to the paclitaxel treatment group, 
these are the adverse events that were increased in the 
Herceptin plus paclitaxel treatment arm.  We observed chills 
and fever and arthralgia that were common to the first dose 
of Herceptin, and insomnia.  We also observed diarrhea, 
cough, tachycardia and accidental injury.  Again, you see a 
similar pattern.  The majority of these events were mild to 
moderate in severity and severe events were infrequent. 
	[Slide]
	We observed some dermatologic adverse events of 
acne and rash, epistaxis, hypertonia, herpes simplex, and 
some infectious complications that were increased with 
Herceptin treatment. 
	[Slide]
	We observed 2 serious adverse events that were 
increased with Herceptin.  Fever was one but the rate of 
dehydration was balanced across the treatment groups. 
	[Slide]
	Sixty-five of the 91 patients who were treated 
with Herceptin in the paclitaxel treatment group 
discontinued Herceptin.  A majority of those, 50 patients, 
discontinuations were related to disease progression, and 6 
patients discontinued for reasons due to an adverse event.  
Three of those adverse events were cardiac in origin. 
	[Slide]
	We assessed 903 patients for immunogenicity to 
Herceptin using an ELISA assay.  We observed only 1 positive 
result.  This patient is a 49-year old woman who was treated 
in the open-label, single-agent H0649g study.  She had 
received 9 doses of Herceptin and discontinued the trial on 
day 65 due to reasons related to disease progression.  A 
serum sample was drawn and the titer was found to be 
positive.  However, upon review of the adverse events at the 
time of discontinuation, there were no events that suggested 
an allergy to Herceptin. 
	[Slide]
	Turning now to the cardiac adverse events, I would 
like to start the discussion by providing you with a 
background of the safety concern, followed by a discussion 
of the procedures and methods used by our cardiac review and 
evaluation committee, and then close with a discussion of 
the results of their assessments by incidence severity, 
outcome and analysis of risk. 
	[Slide]
	A cardiac safety concern was identified after 4 
serious cases of cardiomyopathy were reported to Genentech 
as serious adverse events.  The safety concern was 
unexpected given the prior anthracycline histories in all 4 
cases, but was also unpredicted based on our preclinical 
safety program and our Phase 1 and 2 clinical trial data.
	In response to the safety concern, we provided 
information to our independent data monitoring committee for 
review, and also alerted our investigators, patients and 
regulatory authorities, with amendments to our protocols, 
revisions to our informed consents and investigator 
brochure.  Most importantly, we informed retrospectively an 
independent cardia review and evaluation committee to assist 
Genentech with assessment of the severity of this issue.
	[Slide]
	The cardiac review and evaluation committee was 
charged with defining the syndrome of cardiac dysfunction, 
to determine the incidence and assess the severity using the 
New York Heart Association functional classification scoring 
system at the time of presentation and following treatment.  
The committee was independent of Genentech and not otherwise 
participating in the clinical trial, and were blinded to 
Herceptin treatment exposure.  The committee was comprised 
of 2 oncologists who were specialists in breast cancer and 1 
cardiologist. 
	[Slide]
	The cardiac review and evaluation committee 
prospectively defined cardiac dysfunction to include any one 
of the following characteristics: signs and symptoms of 
congestive heart failure, a cardiomyopathy that was 
characterized by a fall in cardiac ejection fraction with 
hypokinesis that was either global or more severe in the 
septum, and criteria for decline in cardiac ejection 
fraction for both symptomatic and asymptomatic patients. 
	[Slide]
	The CREC used the New York Heart Functional 
Association classification scale to measure the severity of 
cardiac dysfunction at initial presentation and following 
treatment.  For those of you who are not familiar with this 
system, here are the key points.  It is a 4-class system.  
Class I patients have no limitations of physical activity.  
Class II patients have slight limitations of physical 
activity, and ordinary activity can result in symptoms 
related to cardiac dysfunction.  Class III patients have 
marked limitations of physical activity and less than 
ordinary activity can result in symptoms.  Class IV 
patients, the most severe class, are patients who have an 
inability to carry on any physical activity without 
symptoms.  They very often are symptomatic at rest. 
	[Slide]
	Here are the results of the CREC review.  The 
review process was intended to be comprehensive and without 
bias.  The committee provided Genentech with search criteria 
describing cardiac dysfunction.  We then applied that search 
criteria to our safety databases, and provided the cardiac 
review and evaluation committee with patient profiles for 
review that contained adverse events, medications, and 
ejection fractions, and 1024 patients were in the database 
that was screened by this process. 
	Out of this initial screening, the cardiac review 
committee identified 153 patients for complete medical 
review.  The committee was provided with copies of medical 
records and select data from the clinical trial database for 
review.  From those 153 patients, 97 were diagnosed with 
cardiac dysfunction.  Seven patients were determined to be 
not evaluable due to lack of complete data for review, and 
49 patients were diagnosed with conditions other than 
cardiac dysfunction.  Those conditions in many patients 
included arrhythmia, tamponade, etc. 
	[Slide]
	Here is the summary of the cardiac review and 
evaluation committee results by treatment.  Again, there 
were 97 patients diagnosed with cardiac dysfunction.  The 
majority of those patients were participating in the 
comparative study, H0648g, and a smaller number of patients 
were receiving Herceptin as a single agent or in combination 
with other chemotherapies from 3 other smaller studies. 
	Because the H0658g study is a comparative trial 
and contains the majority of data in this data set, I would 
like to spend a couple of minutes discussing the results and 
analysis of patients in this trial. 
	[Slide]
	This slide details the incidence by treatment 
group of cardiac dysfunction.  The patient subgroup with the 
highest incidence was in the Herceptin plus anthracycline 
treatment arm and 27 percent of patients were diagnosed with 
cardiac dysfunction, which is increased over the 7 percent 
incidence in the anthracycline alone treatment group.  We 
also saw an increase in Herceptin-treated patients in the 
paclitaxel cohort and 12 patients were diagnosed with 
cardiac dysfunction compared with 1 patient in the 
paclitaxel treatment group, although the magnitude of this 
increase is not as large as that seen in the anthracycline 
treatment arm. 
	The severity of cardiac dysfunction at the initial 
event is listed here, and 9 percent of patients in the 
Herceptin plus AC treatment group had class IV; 7 percent 
had class III; and 3 percent had class II.  All 3 classes 
were symptomatic at presentation.  Six percent of patients 
were asymptomatic at initial presentation.  We saw similar 
trends in the control arm.  Conversely, in the paclitaxel 
treatment arm there were no patients at initial presentation 
with New York Heart grade 4 cardiac dysfunction.  In fact, 
many of the patients were either symptomatic or mildly 
symptomatic at initial presentation.  It suggests that the 
syndrome that we observed in the anthracycline treatment 
group compared to the paclitaxel group is somewhat 
different.  The syndrome appears to be less frequent and 
less severe at initial presentation. 
	[Slide]
	Here are the results of cardiac dysfunction 
following treatment.  Again, many of the patients at initial 
presentation in the anthracycline treatment group were 
symptomatic, and many of those patients received therapy for 
cardiac dysfunction, most frequently multiple therapies.  
Cardiac dysfunction appears to be responsive to treatment, 
as seen by the shift in New York Heart Association scores.
	Following treatment there was no case of class IV 
cardiac dysfunction; 6 percent of patients had class III, 
and the majority of patients in this group had class I and 
II.  However, we did observe 1 death related to cardiac 
dysfunction in the Herceptin plus AC treatment group.  We 
saw a similar trend in response in the anthracycline alone 
treatment group, and again saw 1 death related to cardiac 
dysfunction.
	[Slide]
	Here are the results post treatment for the 
paclitaxel treatment arm.  Again, many of the patients were 
moderate to mildly symptomatic at presentation, and we saw 
an improvement in those symptoms as seen by the shift in the 
New York Heart functional scores.  Nine percent of patients 
had class I and 1 percent of patients had class II.  
Importantly, there were no deaths related to cardiac 
dysfunction in this treatment group.  It is very difficult 
to compare the treated patients to the control patients due 
to the low percentage of patients with cardiac dysfunction 
in the paclitaxel alone treatment group. 
	[Slide]
	Again, this safety concern was unexpected, and in 
order to try to identify patients who might be at greater 
risk for cardiac dysfunction we performed an exploratory 
analysis using these following baseline characteristics as 
possible risk factors for cardiac dysfunction.  The only 
risk that we identified were patients who were treated with 
Herceptin plus AC.  In those women increased age was 
suggestive of risk. 
	[Slide]
	We observed cardiac dysfunction in the 3 
open-label studies, H0551g, which is the Phase 2 trial; the 
pivotal H0649g study; and the ongoing H0650g study.  These 
are studies of relapsed metastatic breast cancer for these 2 
trials. 
	The incidence of cardiac dysfunction was 
comparable in 2 studies, and much less in the ongoing H0650g 
study.  All patients in these studies, with the exception of 
1 in the pivotal H0649g study, have received prior 
anthracycline.  Patients in the H0551g study have received 
either CAF therapy of CA therapy up to 6 cycles. 
	We did see persistent cardiac dysfunction in some 
patients who were diagnosed with the condition following 
therapy, however, again, these are women with metastatic 
relapse breast cancer who have received prior anthracycline 
treatment.  Importantly, we did observe death secondary to 
cardiac dysfunction in these studies. 
	[Slide]
	So, to summarize the cardiac adverse event 
profile, cardiac dysfunction was observed in 7 clinical 
studies during the Herceptin development program.  The 
greater risk and probability appears to be with Herceptin as 
concurrently administered with AC chemotherapy.  There is a 
lower probability, and the condition appears to be less 
severe when Herceptin is administered with paclitaxel or 
given as a single agent.  Cardiac dysfunction can be severe 
and life-threatening, however, it is responsive to therapy 
as seen by the relatively low incidence of persistent 
cardiac grade III dysfunction in 1 subgroup.
	[Slide]
	To summarize the overall safety profile of 
Herceptin, Herceptin appears to be generally well tolerated 
when administered as a single agent or in combination with 
chemotherapy. 
	Most of the adverse events that we observed were 
mild to moderate in severity, and severe adverse events were 
infrequent.  This includes infusion-related adverse events, 
the majority being chills and fever with the first dose. 
	We did observe an increased incidence in cardiac 
dysfunction when Herceptin is administered in combination 
with anthracyclines. 
	We also observed an increased incidence in a 
variety of other adverse events, the majority of these 
adverse events being mild to moderate in severity.
	Finally, discontinuations for adverse events were 
infrequent for single agents and for Herceptin plus 
paclitaxel.  The higher incidence observed in patients 
treated with Herceptin plus AC appears to be related to the 
syndrome of cardiac dysfunction. 
	[Slide]
	I would like to turn the podium back to Dr. Shak 
who will discuss these risks in combination with the 
benefits. 
Summary of Benefits and Risks
	DR. SHAK:  Thank you.  I will conclude by briefly 
summarizing the benefits, summarizing the risks, and then 
addressing the net clinical benefit.
	[Slide]
	With regard to the benefits of Herceptin as a 
single agent, we have seen that Herceptin induces objective, 
durable tumor responses. 
	[Slide]
	With regard to the benefits of Herceptin in 
combination with chemotherapy, the results of the analyses 
of the randomized, controlled trial indicate that with 
regard to the prospectively defined endpoint of median time 
to disease progression, a statistically significant and 
clinically important difference was observed, both with 
Herceptin plus chemotherapy compared to chemotherapy 
overall, as well as in the AC and in the paclitaxel stratum.
	[Slide]
	Significant benefits of Herceptin were also seen 
with regard to response rate; 	
	[Slide]
	with regard to the duration of response;
	[Slide]
	with regard to the time to treatment failure; 	
	[Slide]
	and, finally, with regard to survival at 1 year.	  
In summary, in this randomized, controlled trial, we saw 
strong and consistent evidence of benefit. 
	[Slide]
	With regard to safety, Herceptin is generally well 
tolerated.  However, adverse events can be expected based on 
our analysis of the results of the controlled trials.  
Infusion-associated symptoms do occur in up to 40 percent of 
patients, usually fever and chills primarily with the first 
infusion. 
	In addition, we have identified an increased 
incidence of a number of other adverse events which can be 
expected.  Most of those adverse events were mild to 
moderate in severity. 
	[Slide]
	Importantly, we identified a risk of cardiac 
dysfunction.  The risk was greatest and the incidence was 
highest in patients treated concurrently with Herceptin plus 
AC, 27 percent, and lower in patients treated with Herceptin 
plus paclitaxel treatment or treatment with single agent 
Herceptin.  It can be expected that with Herceptin plus AC 6 
percent of patients would have persistent class III cardiac 
dysfunction.  The incidence of persistent class III cardiac 
dysfunction is low, as shown, with Herceptin plus paclitaxel  
or paclitaxel alone. 
	[Slide]
	As we think about addressing net clinical benefit, 
the benefits and the risks, we have found that 2 of our 
prespecified endpoints are useful in addressing this issue.  
First, time to treatment failure.  Time to treatment failure 
balances the benefits of the delay in disease progression or 
death against the risks, as indicated by discontinuation of 
study or Herceptin due to adverse events.  In both the Ac 
stratum and the paclitaxel stratum Herceptin significantly 
delayed the time to treatment failure. 
	[Slide]
	Finally, the most important prespecified endpoint 
which integrates benefit and risk is survival.  With regard 
to survival at 1 year, survival at 1 year was significantly 
increased, from 65 percent with chemotherapy alone to 78 
percent with Herceptin plus chemotherapy, with maintained 
quality of life.
	[Slide]
	This survival difference was seen in both the AC 
strata and in the paclitaxel strata. 
	[Slide]
	In summary, for women that have tumors that 
overexpress HER2 and metastatic breast cancer, a 
particularly aggressive form of this disease, an assessment 
of the benefits and risks supports the use of Herceptin as a 
single agent and in combination with chemotherapy.  The 
benefits of Herceptin in combination with anthracycline 
regimens, however, should be carefully evaluated against the 
risk of increased cardiac dysfunction.
	[Slide]
	Finally, therefore, we would conclude on the basis 
of these data that Herceptin is safe and effective for the 
treatment of patients with metastatic breast cancer who have 
tumors that overexpress HER2.
	Thank you, and we look forward to answering 
questions.
Questions from the Committee
	DR. DUTCHER:  Thank you very much.  Are there 
questions for the sponsor from the committee?  Dr. Schilsky?
	DR. SCHILSKY:  Well, it comes as something of a 
surprise to me that you said consistently that you had no 
expectation regarding cardiac events until they occurred.  
So, I am wondering about at least two types of information.  
One is what you observed in the Phase 1 trials.  Was there 
any hint of cardiac toxicity?  Was there any suggestion that 
it might be dose related?
	Secondly, I guess in the pivotal trials, at least 
early on, there was cardiac surveillance built in which was 
then removed and then reinstated. 
	DR. SHAK:  Yes.
	DR. SCHILSKY:  But during the initial portion of 
the trial while there was cardiac surveillance ongoing, was 
there any suggestion that there was cardiac toxicity 
developing in those patients?
	DR. SHAK:  No.  With regard to the questions, 
first of all, our experience in Phase 1 -- we didn't observe 
any cardiac adverse events.  In Phase 2, there were 3 
cardiac adverse events that were judged by the investigator 
and by us to be related to prior anthracycline use.  We did 
assess initially cardiac ejection fractions. 
	In fact, our first DMC meeting occurred in 
September of 1996, after the first 50 or 60 patients had 
been entered into the trial.  They reviewed the unblinded 
data, independent of us, and specifically answered the 
question did they see any increase in the toxicity of 
chemotherapy, and at that early point in time they did not 
report finding an increase. 
	We did actually identify this unexpected event 
through the appropriate and careful monitoring of serious 
adverse events that come in from investigators within 24 
hours of their occurrence. 
	DR. DUTCHER:  Go ahead, Dr. Weiss.
	DR. WEISS:  Dr. Shak, I have a few questions 
regarding the cardiac adverse event issues.  Maybe if you 
could just clarify this, were there baseline ejection 
fractions obtained in a large number of the patients in the 
pivotal studies, pretreatment ejection fractions, by any 
chance at all?
	DR. SHAK:  Actually, Dr. Paton can summarize how 
much we know with regard to ejection fractions.
	DR. WEISS:  Okay.  In the absence of baseline 
ejection fractions, I guess the follow-up question would be 
can one easily evaluate the effect of treatment on the 
presence or absence of any cardiac AEs as well as if you did 
have the ejection fractions?
	You had some numbers for fall in ejection 
fractions, 55 percent minus 5 percent or 10 percent 
depending on symptoms.  Is that an absolute fall or a fall 
from baseline?  So, that is a very full question.
	DR. PATON:  So, your first question, to reiterate, 
is how many patients had baseline cardiac ejection 
fractions. 
	[Slide]
	Here we have a slide that details that level of 
information by the 4 treatment groups.  We have baseline 
data on 13 patients on the Herceptin plus AC, and that is 
the second line on the graph: 23 patients on the AC alone; 
11 patients on Herceptin plus paclitaxel; and 14 patients in 
the paclitaxel alone group.
	DR. WEISS:  So, would you comment on the fall from 
55 percent or 5 percent or 10 percent?  That was then an 
absolute decrement from 55 percent?  Is that correct?
	DR. PATON:  I would like Dr. Deborah Keefe, who 
designed those criteria, to clarify that point for you.
	DR. KEEFE:  Debie Keefe, cardiology advisor to 
Genentech.  That was when we had information available, and 
it was the actual percentage in primarily patients who were 
asymptomatic that we used that.  In some cases there was 
data available that had been obtained for other reasons 
because many of these patients had received anthracyclines.  
In patients who were symptomatic we accepted a single number 
if it was low and correlated with symptoms, even though 
there was not a change. 
	DR. WEISS:  May I ask another follow-up?
	DR. DUTCHER:  Sure.
	DR. WEISS:  Given that, I wonder if either of you 
or any of the three of you might comment on how one might 
accurately assess whether the cardiac adverse events are 
true adverse events, or perhaps a reflection of prior 
disease in some of the patients who didn't have baseline 
echoes, or whether the AE is perhaps potentiated by prior 
disease.  Can you sort that out just a bit?
	DR. PATON:  Dr. Keefe, would you like to comment?
	DR. KEEFE:  To sort it out as best we can, 
realizing that we have incomplete data since it was not 
prospectively collected completely, some of the cardiac 
events do appear to be real.  Certainly, there were true 
clinical syndromes of congestive heart failure.  It is not 
clear that this syndrome is entirely the same as 
anthracycline cardiotoxicity.  In at least some of the 
patients there was much more improvement than you would 
expect from an anthracycline cardiomyopathy.  However, there 
did seem to be an interaction, and the information that is 
actually most supportive of the fact that Herceptin may have 
had a role in this is not any of our preexisting information 
but the fact that it was a randomized trial and we did, in 
fact, see different numbers.  In any given case, these were 
very sick patients who had multiple reasons to have dyspnea 
and symptoms of heart failure.  As you heard, there was an 
overwhelming number who had lung involvement, and separating 
that out could be very difficult. 
	DR. WEISS:  Any thoughts on the mechanism of 
possible interaction between Herceptin and the 
anthracycline, because the AE rate in that particular 
category was so dramatically higher than in patients on 
anthracycline alone? 
	DR. SHAK:  At the current time, we don't have any 
data that directly bears on the mechanism.  That is 
obviously a subject of great interest to us, as well as our 
academic colleagues. 
	DR. DUTCHER:  Dr. Lipschultz, do you have a 
question?
	DR. LIPSCHULTZ:  I also have some questions 
regarding the cardiac findings.  You mentioned before that 
you had a core lab for your HER2 testing for rigor and 
standardization.  Did you have anything similar for cardiac 
measurements, or were those just what was reported?  Did you 
have any quality control for ejection fractions or things 
like that?
	DR. SHAK:  We asked for ejection fractions to be 
obtained either by MUGA or echo but, again, since this was 
unexpected, we did not institute the kind of procedures that 
you are talking about. 
	DR. LIPSCHULTZ:  For the patients on the study -- 
we just saw the data for the numbers who had measurements of 
ejection fraction, did you have numbers for 
electrocardiograms or biopsy or autopsy findings relevant to 
the heart in the sense of trying to better understand this?  
Because at various points in here you speak of tachycardia; 
you speak of arrhythmias; and I am just wondering if you 
have any additional cardiac data along those lines. 
	DR. SHAK:  We actually don't have any additional 
data that would help with regard to that. 
	DR. LIPSCHULTZ:  So, the electrocardiographic 
abnormalities were just those that were randomly reported, 
but it wasn't part of what was collected?
	DR. SHAK:  Correct.  
	DR. LIPSCHULTZ:  At one point, and I think it was 
in the FDA supplied information, there was mention of at 
least histologic appearance of myocardium in one patient.  
Was there additional information in any other patient?  I 
ask the question I was asking before about biopsy or 
autopsy.
	DR. SHAK:  Yes.
	DR. LIPSCHULTZ:  So, clearly, you have at least 
one.  You don't have anything else?
	DR. SHAK:  It is just anecdotal, but there are 
studies that we performed in three cases for which we have 
data with regard to myocardial biopsy, and a fourth.  Dr. 
Paton?
	[Slide]
	DR. PATON:  We obtained the reports on 4 patients 
who had biopsies performed.  One of these patients is from 
the single-agent trial and the remaining 3 patients are from 
the comparative study.  In 3/4 patients there was evidence 
of some damage.  The first patient had received 426 mg of 
anthracycline and her biopsy was consistent with  
anthracycline toxicity.  The second patient had also 
received significant anthracycline, however, her specimen 
was not of a good quality to make any assessment.  So the 
only conclusion was that they could not evaluate it.  They 
saw no evidence of toxicity.  The third patient had received 
2 cycles of AC on study and had a biopsy performed.  There 
was no inflammation, necrosis or fibrosis, but occasional 
vacuoles seen in her specimen.  In the fourth patient there 
was evidence for a grade 1 toxicity.
	DR. LIPSCHULTZ:  Grade 1 anthracycline toxicity?
	DR. PATON:  There was minimal evidence of 
anthracycline damage.  This is directly out of the pathology 
reports that were supplied. 
	DR. DUTCHER:  Why were these people biopsied?
	DR. PATON:  They were biopsied as part of the 
routine care and investigation of the symptoms that were 
reported.  These patients were symptomatic. 
	DR. LIPSCHULTZ:  Getting at some of these 
findings, we are focusing on anthracycline potentiation of 
toxicity, but in the same group they were receiving 
cyclophosphamide as well which could have an inflammatory 
pericarditis.  I notice a couple of your patients were 
listed as having pericardial effusions or tamponade.  I know 
in some of the prior interleukin studies at high dose there 
was potentiation, and these also have effects.  That is why 
I was wondering if you had any more information that you 
could potentially have available from patients to try to get 
a feel for the mechanism.
	The other question I have is that in some of your 
data you speak of improvement in New York Heart Association 
with therapy.  As a cardiomyopathy cardiologist, we usually 
don't find that to be a particularly useful prognostic 
scoring system, and certainly in the field of transplant and 
other things we rely on much more objective criteria. 
	One of the questions that I have for you is most 
patients will respond to therapy for congestive heart 
failure at least transiently.  It was not clear to me from 
you presentation what the interval was between your 
assessment before and after anticongestive therapy?  Because 
part of your conclusion is that most of these patients will 
respond that have congestive heart failure symptoms, and 
what sort of follow-up do you have of these patients?
	DR. PATON;  The duration of follow-up varied by 
the onset and length of participation in the trial.  We 
initiated the cardiac review system in late 1997, and it 
continued through the second quarter of this year.  As far 
as the quality of the response, I would like again to ask 
Dr. Keefe to comment on the quality of the responses that 
she reviewed. 
	DR. LIPSCHULTZ:  But the data that you showed for 
improvement on anticongestive therapy -- it looked like you 
had a cut-off on data of December 31.  I am just wondering 
how long after starting anticongestive therapy did you make 
those slides?
	DR. PATON:  Actually, to clarify, the majority of 
the safety data that I presented today was data with the 
cut-off of December 31.  Some of the cardiac data that we 
obtained was very current and does exceed that cut-off.  So, 
to answer your question about the duration of those 
responses to anticongestive therapy, Dr. Keefe may want to 
comment. 
	DR. KEEFE:  Just one additional comment, when we 
do talk about a longer-term response, we are allowing at 
least 2 visits, which would be a minimum of 2-4 weeks 
depending on the exact trial, after the acute event.  In 
most cases, this was the latest information that was 
available and in several cases many months or years.  
However, the limitation in this trial was really that these 
patients had advanced metastatic breast cancer and that 
disease continued to progression.  So, this is very 
different than our transplant populations where thy don't 
have another complicating factor.  The ones that were not 
available, for example, couldn't be evaluated because they 
developed brain metastases and couldn't walk or had other 
disastrous complications. 
	DR. DUTCHER:  Dr. Weiss?
	DR. WEISS:  Yes, Dr. Lipschultz raises some very 
critical issues in his last set of questions.  I just want 
to follow-up along similar lines.  Many, many patients with 
severe cardiomyopathies and tremendous ejection fractions, 
as Dr. Lipschultz implied, respond dramatically to very 
straightforward anticongestive heart failure measures, and 
sometimes durably, and improvement in symptoms doesn't often 
equate with marked improvement structurally or even 
functionally by objective criteria. 
	I would just like to follow-up on the objective 
criteria question a little bit.  Do you have any follow-up 
information, for example, on follow-up echocardiograms in 
those patients who did versus those patients who didn't 
improve?  Was there improvement in ejection fraction by some 
objective means?  And, finally, were there any particular 
agents that were particularly efficacious in making these 
patients better, any particular class of agents over other 
classes? 
	DR. SHAK:  With regard to the cardiac ejection 
fraction data, again very simply, we did see in the data set 
some cases in which the ejection fractions did improve with 
therapy and in some cases they did not.  With regard to 
treatment, Dr. Paton can address that.  The CREC also did 
document treatment in all of these cases.
	DR. PATON:  We observed combination therapies 
employed commonly for the patients in the Herceptin plus AC 
treatment group.  The common combinations were digoxin plus 
a diuretic, most often Lasix, and an ACE inhibitor.  That 
was a very common combination that we observed in the 
Herceptin plus AC treatment group.  Only 2 patients required 
either dopamine dibutamine for control.  In contrast, the 
patients who developed cardiac dysfunction in the Herceptin 
plus paclitaxel treatment group were treated with single 
agents for the majority, either diuretics or an ACE 
inhibitor.  Digoxin was not a common agent in the Herceptin 
plus paclitaxel treatment group. 
	DR. WEISS:  Just a final question, did many of 
these patients or any of them respond to prior pretreatment 
with dexrazoxane?
	DR. PATON:  Dexrazoxane was administered primarily 
to patients who were in the AC treatment cohort.  It was 
administered after approximately 300 mg/m2 which is 
consistent with the labeling with dexrazoxane.  We could 
show the slide to see the distribution between the cardiac 
versus the non-cardiac patients.  In patients with cardiac 
dysfunction, 5 patients received Zinecard.  In patients 
without cardiac dysfunction, 7 in the Herceptin plus AC 
group compared to 4 in the AC alone group.  We did not 
control for Zinecard usage in our protocol. 
	DR. DUTCHER:  Dr. Vose?
	DR. VOSE:  I have a couple of questions on a 
different topic, to change topics for a minute.  In patients 
with breast cancer and bone disease it is sometimes very 
difficult to assess their response to therapy.  Can you tell 
me the criteria that they used as far as assessment of 
complete response and partial response for those patients, 
and what percentage of the responders had bone disease alone 
or a major part of their disease as bone disease?
	DR. SHAK:  In the H0649g study, the single-agent 
study, patients with bone-only disease were enrolled. 
	DR. VOSE:  In the other studies?
	DR. SHAK:  In the comparative trial we did allow 
bone-only disease, which is the case in about 8 percent of 
cases.  So, it was very small.  With regard to the 
assessment, which is the most important issue of progression 
or response in bone, there was a requirement in the response 
evaluation charter as well as a requirement for the 
investigators to document bone disease if it was to be an 
indicator lesion by objective criteria, most preferably an 
MRI or a CT scan.  So, it was those studies then that were 
provided to the CREC for their assessments. 
	DR. VOSE:  You were using MRI and CT scans --
	DR. SHAK:  Right.
	DR. VOSE:  -- the combination is somewhat 
difficult because you always have lesions that are left over 
and you don't quite know what they mean.
	DR. SHAK:  Right.
	DR. VOSE:  So, that is difficult criteria.  So, 
you are saying for a complete response in bone-only disease 
you required that they had absolutely no evidence of 
abnormality?
	DR. SHAK:  Our definition of complete response was 
no evidence of disease.  I think there was one case in which 
that might be questioned in the single-agent study. 
	DR. VOSE:  And one other question with respect to 
patients.  In some of the other similar antibody studies, 
patients that had failed transplant paradoxically actually 
had an improved response to the antibody studies, such as 
the C2B8 study and the B1 study.  Did you look at that as 
prognostic criteria, in particular in the paclitaxel group?  
Did that account for some of the differences? 
	DR. SHAK:  We actually looked at that in both 
studies, and that paradoxical effect actually was observed 
in a single-agent study.  In that study, the overall 
response rate was 15 percent.  But in 26 percent of the 
patients, almost a quarter that had a prior transplant the 
response rate was over 25 percent.  With regard to the 
comparative trial in prior transplants, we have it in terms 
of risk ratios of response, we will get that for you.
	DR. DUTCHER:  Could I ask you a little bit about 
the infections that seemed to be at a higher number in the 
group that received Herceptin?  Did you explore that at all?  
Is it a function of some type of immunological interaction 
or pure chance, or whatever?
	DR. SHAK:  We have characterized the nature and 
severity of the infections. 
	[Slide]
	DR. PATON:  As I previously presented, we observed 
an increase in infection in Herceptin-treated patients.  For 
those adverse events that were consolidated under the term 
"infection" we observed 2 primary types of infection.  The 
first was upper respiratory tract, colds, viral type 
illnesses that were easily managed with over-the-counter 
cough and cold products.  Those wee mild and moderate in 
severity.  We also observed catheter-related infections that 
were probably related to the increased frequency of catheter 
manipulation for the antibody infusion.  Again, many of 
these infections were easily managed with antibiotics and, 
in rare cases, removal of the indwelling catheter. 
	DR. DUTCHER:  Dr. Miller?
	DR. MILLER:  Just getting back to the incidence of 
toxicities, you talked about that the cardiac events were 
unexpected and I want to go back to your Phase 1 and Phase 2 
study designs.  Did you do dose-limiting toxicity in the 
Phase 1 study?
	DR. PATON:  No, we did not. 
	DR. MILLER:  Then, your Phase 2 studies used a 
different drug, combination of cisplatin and Herceptin, than 
your pivotal studies.  So, the cardiac finding was 
unexpected in a large trial, I think in some ways, because 
the Phase 1 studies didn't look at the same population.  So, 
now we are left with trying to determine what chemotherapies 
we can and can't potentially use in combination with 
Herceptin.  Do we need to do Phase 1 with this drug because 
we didn't pick this up? 
	Also, as Dr. Lipschultz said, this is not cytoxan, 
as you said, and as you dose escalate cytoxan potentially if 
you want to use these drugs potentially, it is the 
anthracycline in the AC, not the cytoxan, and how are we 
going to get that information?  Can you just sort of give me 
an idea of the background about going into a Phase 3 with 
something that wasn't tested in Phase 2?
	DR. PATON:  I would like to ask Dr. Shak to 
explain the development and rationale.
	DR. SHAK:  A selection of the combination with 
cisplatin in the Phase 2 was based on very strong and 
compelling preclinical data.  However, it was also clear 
that in doing a randomized study it would be difficult to 
get patients in a control arm to randomize currently to that 
agent alone.  Therefore, we did, in collaboration with our 
advisers and the FDA, design an appropriate trial that was 
relevant to answering the question of does the addition of 
Herceptin add benefit to available regimens that are 
commonly used. 
	With regard to the issue of how do we assure 
safety, that was again one of the reasons why we 
specifically had the data safety monitoring committee review 
safety after the first 60 patients.  It was, in part, to be 
diligent about safety in that regard. 
	With regard to the question about safety with 
other chemotherapeutic agents, again the best way to 
evaluate safety is in controlled studies in which safety and 
ultimately efficacy is carefully established. 
	DR. MILLER:  I have a follow-up question.  In the 
randomized trial you changed your screening criteria with 
the second amendment and put it back in the third.  Does 
screening for cardiac dysfunction affect the incidence of 
cardiac AEs?  I mean, there was a time period where there 
was really no real screening.  The patients could be as sick 
almost as they wanted to be as long as the investigator felt 
that he could -- I mean, the wording for when those patients 
could go on study was very vague, and I know that was 
because you wanted to open enrollment.  But is that the time 
period of the study that was at greatest risk, and when you 
actually then went back and added some more cardiac 
screening did your risk go down?
	DR. SHAK:  We did carefully look at the 
demographics of patients enrolled in the study, and with 
regard to eligibility, and although there was a handful of 
cases that might have been enrolled in the study, because of 
the change in the eligibility criteria when we looked at the 
incidence of cardiac dysfunction we saw no relationship to 
prior disease as being a predictor.  So, in that regard, I 
don't think that there is a relationship.  We did pick up 
this as an adverse event by doing appropriate and careful 
clinical monitoring both by our investigators and by us.
	DR. MILLER:  But I guess the question is what was 
the incidence early on when you were doing monitoring 
comparing to the incidence when you weren't doing 
monitoring?
	DR. SHAK:  Oh, we picked this up mainly related to 
the rate of enrollment in the study.  As the rate of 
enrollment in the study increased, the number of patients on 
Herceptin plus AC increased.  That was then precisely the 
point where it went from being just 1 or 2 cases, which is 
all we were aware of, to being I think at that point 8 at 
the time at which we decided that this was very much a 
possible risk.  So, it was the rate of enrollment that drove 
our recognition and not the change in eligibility per se.
	DR. MILLER:  Okay.  So, we don't have any way we 
can sort of figure out which patients would be at greatest 
risk.  So, a good screening for MUGA or ejection fraction 
going into a study, we don't think could be of any help?
	DR. SHAK:  We don't have data at this point.  We 
have looked at whether we could predict this and, as Dr. 
Paton presented, when we looked at risk factors at this 
point, the only risk factor that was identified was in the 
subgroup of women who were treated with Herceptin plus AC 
and were of older age. 
	DR. DUTCHER:  Miss Beaman?
	MS. BEAMAN:  I think I saw standard dosage.  Was 
the dosage of Herceptin always standard or the same whether 
it was used alone or with chemotherapy, and would that have 
made a difference in varying that dosage in terms of 
toxicity?
	DR. SHAK:  The dosage that was used in both 
studies was the same.  So, we have evidence that addresses 
the safety and efficacy at the recommended dose.  We don't 
have data to address safety and efficacy at alternative 
doses. 
	DR. DUTCHER:  Dr. Simon?
	DR. SIMON:  I have a couple of questions.  One, 
and maybe I missed it, what was the response rate in the 
comparative trial to the patients who crossed over to the 
Herceptin arm?  And, what was the nature of their treatment?
	DR. SHAK:  The question is about the patients 
enrolled in the crossover study, H0659g.  What was the 
nature of their treatment?  We did, in fact, allow standard 
chemotherapy so a large number of regimens were employed in 
these patients. 
	DR. SIMON:  I am talking about the patients who 
initially were randomized not to receive Herceptin and then 
they progressed --
	DR. SHAK:  Right, we will have a slide in a second 
that will show at least the most commonly used agents, and 
then there were many other regimens. 
	DR. SIMON:  So, some of them received Herceptin at 
crossover.
	DR. SHAK:  Yes, they could receive Herceptin at 
crossover either alone or in combination with other 
regimens.  With regard to your second question about the 
response rate in the crossover, the response rate overall --
	DR. SIMON:  Those who received Herceptin at 
crossover. 
	DR. SHAK:  Yes, the response rate was 14 percent.
	DR. SIMON:  The other question I have had to do 
with survival data.  It is very unusual in therapeutic 
oncology studies to use 1-year survival as sort of the 
endpoint.  Usually you use survival as the endpoint.  In 
fact, a lot of times when people use 1-year survival it is 
actually very suspicious because people tend to pick the 
point where the curves are maximally separated post hoc.  
You indicated that this was defined as an endpoint in the 
protocol.  Is that correct?
	DR. SHAK:  This was prespecified.
	DR. SIMON:  And what was the rationale?
	DR. SHAK:  The rationale was really two-fold.  The 
first was that survival at 1 year is clinically important to 
patients who are HER2 positive with metastatic breast 
cancer.  The second point did reflect the fact that we knew 
that there was a crossover and that might mitigate the 
interpretation of data with long-term follow-up. 
	DR. SIMON:  Did you have patients on the study who 
were on study for less than one year, who at the time of 
analysis had entered the study within the previous 12 
months?
	DR. SHAK:  I don't understand the question.
	DR. SIMON:  At the time of analysis, I guess it 
was April -- well, when did your accrual close?
	DR. SHAK:  The accrual closed in March of 1997, 
and we did our analysis in March of 1998.  So we had good 
follow-up.
	DR. DUTCHER:  Dr. Doroshow?
	DR. DOROSHOW:  I have two questions.  Could you 
tell us whether or not left chest wall irradiation was 
evaluated as a risk factor for cardiac toxicity?
	DR. SHAK:  Chest radiation was evaluated --
	DR. DOROSHOW:  Left chest wall irradiation, not 
irradiation therapy as a whole?
	DR. PATON:  The data that we collected included a 
history of radiation therapy, and when the questionnaire was 
answered "yes" and the patient had left breast disease, we 
evaluated that as being radiation therapy in the adjuvant 
setting to the left side.  We also included mediastinal 
radiation in that assessment. 
	DR. DOROSHOW:  In that assessment as separated 
from the totality of patients getting radiation therapy, was 
that a risk factor or was it not?
	DR. PATON:  It was not a risk factor in our 
analysis.
	DR. DOROSHOW:  Okay, and could you tell us whether 
you systematically evaluated whether or not the 
reinstitution or the continuation of single-agent antibody 
in patients who had had previous combination chemotherapy 
and antibody was itself a risk factor for the development of 
cardiac toxicity?
	DR. PATON:  Actually, the best setting to evaluate 
that is in the roll-over study from the pivotal H0648g 
study.  We do have data on the number of patients from the 
AC control arm.  I think this is your question and please 
correct me -- no, it is not your question?
	DR. DOROSHOW:  The question is not whether or not 
there was reinstitution of antibody after patients had AC, 
it is whether patients continued.  Some of those patients 
had had it before and continued antibody.  The further 
exposure to additional antibody, was that itself a risk 
factor?
	DR. PATON:  No, by and large, that was not a risk 
factor.  Many of the patients in the Herceptin plus AC 
treatment group discontinued for reasons of the cardiac 
event, and those patients who continued, their conditions 
did not appear to worsen either by physician assessment, 
changes in medication and so forth.  So, the majority of 
patients appeared to do well with reinstitution of antibody.
	DR. DUTCHER:  Dr. Margolin?
	DR. MARGOLIN:  I have some questions that are all 
in some way or another related to HER2/neu expression on 
breast cancer.  The first question is that I think somebody 
said that in the single-agent study there was an apparently 
higher response rate, although I don't know what the p value 
was for the small subgroup of patients who had undergone 
transplant, and I wonder if anybody went back and found that 
that correlated with the high level of HER2/neu expression 
since those may be patients who presented with higher risk 
multiple node disease.
	DR. SHAK:  I don't think we have the ratio of 2+ 
to 3+ in the patients with prior transplant. 
	DR. MARGOLIN:  Okay.  The other related question 
is there has been a rumor around, and I don't know how far 
around it has gone, that there is a possibility that 
metastatic lesions are more likely to express HER2/neu than 
primary lesions.  I think most of us screen only the primary 
blocks and I assume that is what was screened in this study.  
So, it is sort of a two-part question.  I wonder if there is 
any validity to that.  Then, the second part is that at some 
point I guess we are going to have to talk about the 
screening test for HER2/neu positivity that is going to be 
recommended for patient treatment selection, and the 
difference between the outcomes of patients who were 3+ 
positive and patients who were 2+ positive. 
	DR. SHAK:  Dr. Slamon, could you address the issue 
of HER2 positivity?
	DR. SLAMON:  To my knowledge, there have been two 
large studies looking at metastatic and primary lesions, and 
there is no difference between metastatic lesions versus 
primary lesions.  I have heard the same rumor, but when you 
look critically at the data that is published, as well as 
some of the banks that people have, and we have a pretty 
extensive bank also, that doesn't appear to be the case.  
What is in the primary is in the metastasis.  If it is a 
single copy, it remains a single copy.  If it is multiple 
copy, it remains multiple copy at the same level. 
	DR. DUTCHER:  Dr. O'Leary?
	DR. O'LEARY:  Yes, I would like to follow-up on 
some of these issues having to do with getting the patient 
into the study in the first place.  I apologize if they seem 
not germane but they may be relevant to the meeting on 
Friday as well.
	How many different sites -- not meaning body sites 
but clinical sites, did the initial biopsy materials come 
from for evaluation by the core laboratory?
	DR. SHAK:  For the vast majority of patients, the 
analysis at the core laboratory was done on the original 
tumor blocks from the primary diagnosis.
	DR. O'LEARY:  Right, but I am asking how many 
different hospitals or medical centers had these blocks been 
originally --
	DR. SHAK:  I don't know the exact number but I am 
sure very many. 
	DR. O'LEARY:  One of the things that affects the 
ability to assess things immunohistochemically is 
differences in fixation protocols, time in which things 
remain in fixative.  Was there any evidence of heterogeneity 
from one site to another in the percentage of patients whose 
tumors appeared to be HER2 expressors?
	DR. SHAK:  Our pilot studies identified some of 
those same concerns with regard to slides.  So, it was for 
that reason that with regard to this study we requested 
original tumor blocks and, therefore, at the core laboratory 
sectioned and stained them in a reproducible manner. 
	DR. O'LEARY:  But that handles the determination 
after its gotten into the paraffin block, and 
immunohistochemistry is a total test system in which the 
treatment of the tumor prior to the time that it hits 
paraffin is also important in some cases in determining 
immunoreactivity.  In particular, because the test system 
that you used in this study is different than the test 
system coming up on Friday, and because that won't be 
assessed against original patient response data it is really 
vital to understand, to the degree possible, whether any of 
these sort of pre-analytic factors can be discounted.
	DR. SHAK:  The pre-analytic factors, as I said, 
were not controlled but I guess the good news here is that 
we did, in fact, simulate what will likely be real-world 
testing as we go forward. 
	DR. O'LEARY:  The second set of issues is that in 
real-world testing sometimes people will end up using 
different tests than the ones that FDA may have approved to 
go into patient selection.  I mean, we heard a letter, for 
example, from a FISH laboratory and this is popular in some 
places.  There are a number of different antibodies against 
HER2/neu.  Have you explored any of these in your 
investigations?
	DR. SHAK:  We have no data on the use of FISH or 
any of those other technologies. 
	DR. O'LEARY:  Okay.  And, the last question is 
sometimes in patients that present with metastatic disease 
assessments are being made on the basis of cytologic 
preparations, fine needle, and the question is has 
fine-needle aspiration as a source of material ever done in 
the course of any of these investigations?
	DR. SHAK:  I am sorry, could you repeat that?
	DR. O'LEARY:  Were fine-needle aspiration 
specimens used in the determination of immunoreactivity in 
any of these cases, or were they all regular biopsy tissue 
blocks?	
	DR. SHAK:  In my recollection, the vast majority 
were tumor blocks.  There were fine-needle aspirates but the 
core laboratory tested their procedure with regard to those 
fine-needle aspirate samples as well.
	DR. O'LEARY:  Thank you. 
	DR. DUTCHER:  Last question, Dr. Schilsky?
	DR. SCHILSKY:  Maybe I can squeeze in two 
questions.  First an efficacy question, in the randomized 
trial, and specifically in the paclitaxel portion of the 
randomized trial, it is somewhat striking that the response 
rate to paclitaxel alone in a group of patients getting 
essentially first-line chemotherapy for metastatic disease 
is 17 percent.  It is also striking that when you add 
Herceptin which by itself has very little activity in 
metastatic disease, albeit in a more advanced patient 
population, the response rate zooms up to 41 percent.  So, I 
am wondering if you could help us interpret those data, both 
with respect to why is the response rate so low to 
paclitaxel alone, and why is it so much better when 
Herceptin is added. 
	DR. SHAK:  Dr. Norton, would you like to address 
this?
	DR. NORTON:  The answer is that these are the 
data.  I mean, this is what happened.  And, the nice thing 
is that it corroborates what was seen in preclinical 
systems.  I mean, there was true synergy, not just an 
additive effect.  The biochemical mechanisms for this still 
remain obscure but it is a major component of our program to 
try to figure that out.  But, clearly, in the preclinical 
systems there was synergy between these agents, not just 
additivity.  I think the clinical data that you see here 
really substantiates that. 
	DR. SCHILSKY:  The synergy may explain why it is 
better when you add Herceptin but why is it so bad with just 
paclitaxel?
	DR. NORTON:  Again, you know, this is why one does 
randomized trials, because you can't anticipate what the 
response rates are going to be.  As Rich Simon told me many 
years ago, you can't argue with a p value.  You know, the 
fact is that these were very poor prognosis patients, as you 
can see.  Many of these patients really had extensive 
therapy in the adjuvant setting and very poor prognostic 
factors, and were quite sick with a lot of disease, and so a 
very low response rate to paclitaxel in that very sick 
patient population is not totally unexpected. 
	DR. SCHILSKY:  If I can just ask one other 
question about the cardiac toxicity because I still don't 
have a real good sense of just how sick the patients were, 
particularly those who were on Herceptin with AC.  You 
showed us data about the incidence of cardiac toxicity at 
the time it was diagnosed and at the time after treatment.  
But how bad did it get?  In other words, after it was 
diagnosed it might have gotten worse before it got better.  
So, do you have any data on the worst case, the worst 
cardiac toxicity that was observed?  And, for those patients 
who improved, they all improved pretty much to some extent, 
but those patients who had persistent clinically symptomatic 
cardiac toxicity, how long did that last?  Did it last for 
the rest of their lives?  And, on average, how long was 
that?
	DR. SHAK:  Dr. Keefe, again, you reviewed the 
medical records for all of these patients. 
	DR. KEEFE:  You will hear more information about 
the worst point coming up, but it was, in fact, very similar 
to the presentation.  Most of the people were symptomatic at 
rest, not constantly necessarily.  Some did transiently get 
worse and then got better.  Overall, most of them did 
improve substantially, and it was the breast cancer that 
further interfered with the qualify of their life.  There 
were, particularly in the Herceptin plus AC arm, some 
patients that had real significant heart failure despite 
therapy. 
	DR. DUTCHER:  Thank you.  What is your pleasure?  
Break or keep going?  Break?  Short break, five-minute 
break. 
	[Brief recess]
	DR. DUTCHER:  I think that we will begin. 
FDA Presentation
	DR. JERIAN:  My name is Susan Jerian, and I am 
pleased to present the FDA perspective on the biologic 
license application for Herceptin, submitted by Genentech.
	[Slide]
	This BLA was filed May 4, 1998, and I just want to 
go through briefly the series in which we have received the 
data, which has been in a rolling fashion prior to that date 
and, in fact, after that date.  The efficacy supplement was 
submitted May 22, 1998; safety update, July 7, 1998; another 
efficacy update which, in fact, was information that we 
requested on the additional patients that we asked the 
sponsor to go back and analyze, who had not been analyzed 
yet by the REC, was received just a week and a half ago.  We 
have completed those analyses in a week and we will present 
those data here today.  Additional information is being 
requested by the FDA and we are awaiting that in order to 
complete our review.
	[Slide]
	Genentech's proposed indication for Herceptin 
reads as follows:  Herceptin is indicated for the treatment 
of patients with metastatic breast cancer who have tumors 
that overexpress HER2.
	[Slide]
	The clinical studies that I will be concentrating 
on and devoting 99 percent of my presentation to are 649, 
the Phase 2 study with Herceptin as a single agent enrolling 
222 patients, and 648, the Phase 3 study which was a 
randomized, open-label study comparing chemotherapy with and 
without Herceptin enrolling 469 patients. 
	[Slide]
	There were additional reports from other studies 
submitted to the BLA.  There wee 3 Phase 1 studies --
	[Slide]
	-- and 4 additional Phase 2 studies, 2 of which 
still remain open to enrollment:  650 is a study of patients 
receiving Herceptin as a single agent for first-line therapy 
and 693 is the expanded access trial which you have already 
heard about.
	[Slide]
	In my presentation, first I will provide you with 
our review of our design and efficacy results for the Phase 
2 and then for the Phase 3 study.  Following this, I am 
going to present an integrated summary of the 
immunohistochemistry data as it relates to the efficacy 
endpoints for the Phase 2 and Phase 3 study, and then an 
integrated safety summary, finishing with my conclusions. 
	[Slide]
	As you have already heard, this Phase 2 study, 
submitted for consideration, is a single-arm study of 
Herceptin, conducted at 54 sites internationally with a 
target enrollment of 200 patients.  Those patients enrolled 
had metastatic breast cancer with measurable disease, and 
had to have been positive on their tumor biopsies for 
expression of HER2/neu protein by immunohistochemistry at 
the level of 2+ or 3+.  Patients must have progressed after 
1 or 2 prior chemotherapy regimens for their metastatic 
disease. 
	[Slide]
	I will not go over this slide.  You have already 
received this information on the dosing.
	[Slide]
	Once a patient progressed on the study, they had 3 
choices.  They could discontinue treatment; they could 
continue to receive Herceptin at the same dose with or 
without chemotherapy or hormonal therapy; or they could 
continue with Herceptin at double the dose with or without 
chemotherapy or hormonal therapy.  The additional therapy 
was not given in a randomized fashion.  It was simply left 
up to the patient and their physician. 
	[Slide]
	The primary endpoint was overall response rate, 
which was defined as the sum of the complete and partial 
responses which had been sustained for at least 4 weeks as 
defined by the response evaluation committee.  The secondary 
endpoints were duration of response, time to progression, 
time to treatment failure and survival.
	[Slide]
	You have already heard a great deal about the 
response evaluation committee.  I just want to point out a 
couple of factors.  I think the committee functioned quite 
well and they stuck to their charter very consistently, and 
did a very good job in assessing tumor measurements or scans 
that were supplied to them and information that was supplied 
to them in a consistent fashion. 
	Their character was somewhat limited in that they 
could not call pleural effusions or ascites as malignant 
effusions unless they had pathologic evidence of disease.  
In addition, bone disease evaluations were somewhat limited 
in that physicians were not requiring all sites of bony 
disease unless patients were symptomatic at the sites.  So, 
we don't always have follow-up information on bony sites of 
disease, except in the patients who have bone-only disease 
where there was good follow-up.  Finally, the size of 
lesions was limited to 1 cm but there are many patients who 
have lesions right at that cut-off.  As you know, with CT 
scans sometimes a 1 cm lesion can be missed on subsequent 
scans, and at times that makes tumor assessment difficult. 
	[Slide]
	There were 222 patients enrolled, and 213 of these 
received treatment.  If we look at reasons for treatment 
discontinuation, 7 percent stopped due to death; 5 percent 
by patient request; and 3 percent for adverse events; 1 
patient was lost to follow-up.
	[Slide]
	Looking at the baseline demographics, you can see 
that this group had a fairly high incidence of poor 
prognostic factors.  A third were ER/PR negative, had 
progressive disease less than a year from their primary, and 
two-thirds had positive lymph nodes at their initial 
diagnosis. 
	[Slide]
	In terms of prior therapy, one-third had received 
1 regimen of chemotherapy for their metastatic disease, and 
two-thirds had received 2 prior regimens.  A quarter of 
patients had received transplant.
	[Slide]
	Now we have the efficacy results, the primary 
endpoint of overall response rate.  This is the FDA analysis 
based on our review of all the case report forms, data 
submitted from the REC, in addition to adverse event 
reporting.  Our numbers, as I will point out in a minute, 
differ slightly from the sponsor's and I will explain those 
differences. 
	The overall response rate was 14 percent with a 
median duration of response of 9 months.  Of these, 3 
percent of patients were complete responders, and we have 
not been able to give a point determination for median 
duration at this time due to immaturity of the data.  The PR 
rate was 11 percent.
	[Slide]
	The patients in whom there is a difference, and 
actually one of these patients we do agree on now -- 2 of 
the sponsor's patients whom they called CR, complete 
response, we called partial response. 
	The reason for 1 patient is that she had a 
persistent pleural effusion without evidence of congestive 
heart failure, without evidence of ongoing infection, no 
other etiology, and at her because evaluation it was deemed 
as a site of metastatic disease but the REC couldn't call it 
that because they didn't have the pathology. 
	One patient had bone metastases at enrollment but 
was never imaged after baseline.  So, we could not call her 
a CR. 
	There were 3 patients that the sponsor called 
partial responses that we called non-responders or, in fact, 
were not evaluable for response.  Some of that had to do 
with technical reasons.  One person actually received 4 
separate regimens of irradiation therapy to 4 different bony 
sites of disease over a 5-month period, and we felt that 
that may be clinical evidence of progression and so we 
didn't feel comfortable calling her a responder.
	[Slide]
	The median duration of response, as I mentioned, 
was 9 months, and this gives you a little bit more of a feel 
for the distribution of the data.  For the complete 
responders I have listed the individual durations, and for 4 
of those patients, as you can see, we don't have complete 
follow-up.  Those are the asterisk patients.
	[Slide]
	Median time to progression was a secondary 
endpoint, and was 3.1 months; time to treatment failure, 2.3 
months; and median survival was 12.8 months.
	[Slide]
	This is a Kaplan-Meier plot of the survival for 
patients in the Phase 2 study.  The aqua lines are the 95 
percent confidence intervals and the yellow line is the 
survival curve.  Basically, this is not a comparative study 
so we really can't say anything more than that this is 
simply the survival for this population. 
	[Slide]
	So, in summary of the Phase 2 study, the overall 
response rate was 14 percent, with a median duration of 
response of 9 months, and a median survival of 12.8 months.
	[Slide]
	I am not going to go into too much of the study 
design for the Phase 3 study since you have heard a great 
deal about it.  I will mention that patients were randomized 
by geographic region, metastatic site and prior 
anthracycline therapy.  Also, I will refer to Taxol as 
paclitaxel but I think Taxol is maybe known to more people 
than paclitaxel.
	[Slide]
	Patients enrolled in this study were to have 
metastatic breast cancer with measurable lesions.  Again, 
they had to be 2+ or 3+ positive by immunohistochemistry, 
and have received no prior chemotherapy for metastatic 
disease.  Patients could have brain metastases if they were 
stable and treated, and there was a general statement about 
eligibility where patients must be suitable candidates for 
receiving concomitant cytotoxic chemotherapy as evidenced by 
screening lab assessments of hematologic, renal, hepatic, 
and metabolic function.
	[Slide]
	I think you have already heard a great deal about 
treatment.
	[Slide]
	When a patient progressed on this study, they had 
2 choices.  They could discontinue or they could enroll into 
study 659, which was the extension study for 648.  On 659 
patients could receive Herceptin with or without 
chemotherapy or hormonal therapy, and this was up to the 
investigators, not in a randomized fashion. 
	[Slide]
	The primary endpoint, as you have already heard, 
was median time to progression, and secondary endpoints were 
overall response rate, duration of response, time to 
treatment failure, survival and quality of life.  I will not 
be commenting on the quality of life data at this point 
because our analysis is not complete. 
	[Slide]
	I want to take a moment to discuss the differences 
that occurred in the trial as it proceeded in terms of study 
design.  You have already heard some of these things 
mentioned in that the original protocol was modified in 
order to increase enrollment and make it more attractive to 
breast cancer patients to participate in the study.  As you 
know, Taxol was added as an option for chemotherapy. 
	As far as immunohistochemistry staining, initially 
one antibody was used, the 4D5 antibody which is the parent 
antibody to Herceptin.  Subsequently another antibody, CB11, 
was added and patients could be positive with either/or 
antibody. 
	Bone-only disease was initially not included, and 
subsequently allowed provided lesions were lytic and 
measurable in 2 dimensions.  Brain metastases were not 
initially allowed and subsequently included if patients had 
received treatment and had stable metastases in the brain.
	[Slide]
	Cardiac assessment, as you heard, was required at 
baseline but not subsequently, and then further amended, as 
you heard, after that.  Laboratory cut-offs were defined 
clearly in the beginning and subsequently eliminated.  The 
statement that I read to you earlier was put in its place.  
Tumor assessment time points were increased by a few weeks 
and that is somewhat relevant to time to progression 
determinations.  Initially there was no crossover study, the 
659 study.  That was added to allow breast cancer patients 
who wished to receive Herceptin the opportunity to do so 
after they had progressed if they were on the control arm.  
Subsequently that was put in effect.
	[Slide]
	I want to point out that some of these changes 
lead to issues that are relevant to the analysis of the 
data.  First, the patients treated with paclitaxel had very 
different prognostic factors and, as you have already seen, 
were a different population.  Therefore, we had to rely 
heavily on subgroup analyses. 
	Eligibility criteria were broadened considerably.  
There was a lack of baseline cardiac data for all patients.  
For some patients we did have it, but that made assessment 
of risk factors for cardiotoxicity very difficult. 
	The survival analysis is limited by the fact that 
patients did cross over and received Herceptin.  So, we 
can't say after the crossover that the effect was solely due 
or not due to Herceptin. 
	[Slide]
	There were 469 patients enrolled in 118 sites.  
Most sites had less than 5 patients enrolled.  Five patients 
were not treated, 2 on the Herceptin arm and 3 on the 
control arm.
	[Slide]
	These are the figures for enrollment.  The first 2 
rows are Herceptin plus chemotherapy and chemotherapy alone.  
You can see equivalent enrollment basically.  Then, for the 
subgroups, AC-Herceptin, AC alone, paclitaxel-Herceptin and 
paclitaxel alone.  As you can see, about 40 percent of the 
patients received Taxol and 60 percent AC. 
	[Slide]
	The data that we have received, which has an 
earlier cut-off, shows that 33 percent of patients had 
enrolled into this extension study.  Most of those are from 
the control arm.  We haven't received the updated data.  
There are additional patients who have been enrolled since 
that time.
	[Slide]
	There were 11 patients whom we categorized as 
early deaths in that they died within the first 30 days of 
the study.  In our analysis of cause of death not due to 
Herceptin, 7 were in the Herceptin arm and 4 in the control 
arm.  These patients in general were extremely ill at entry 
and, in many cases, did not meet the "spirit" of the patient 
selection criteria.
	[Slide]
	You have seen this data already on the baseline 
demographics for the randomized groups -- Herceptin plus 
chemotherapy versus chemotherapy alone, so I am going to go 
on to the next slide.
	[Slide]
	It is quite balanced between the 2 groups.  This 
is prior therapy.
	[Slide]
	The main difference I want to point out is when 
you compare those patients who received AC therapy versus 
those who received paclitaxel.  There are marked differences 
in prognostic factors and prior therapy.  The number of 
patients who had positive lymph nodes is nearly doubled.  
More patients had mastectomy.  This is all increased in the 
paclitaxel group.  Nearly double the number of patients who 
received prior adjuvant chemotherapy, and no patients in the 
AC group received transplant, whereas 18 percent of the 
paclitaxel patients had.
	[Slide]
	Sites of metastatic disease was a stratification 
factor, however, the definition that the sponsor used 
differed somewhat from what we interpret as standard 
practice in clinical trials in oncology in that lymph node 
disease, distal lymph node, supraclavicular nodes were 
classified by the sponsor as visceral disease.  We classify 
that as soft tissue or superficial disease.  So, we repeated 
the analysis just to ensure that those factors were 
comparable throughout and, in fact, they were on our 
reassessment.
	[Slide]
	Non-protocol defined chemotherapy or hormonal 
therapy was considered a protocol violation on this study.  
There was a slight imbalance in that more patients on the 
control arm received such therapy, primarily cytotoxic 
chemotherapy, and this was a variety of regimens that the 
investigator chose to give to the patient.
	[Slide]
	We also looked at possible differences in 
cumulative dose, and the most striking data was for the 
paclitaxel groups where the median number of cycles was 
greater by 1 in the paclitaxel-Herceptin subgroup compared 
to Taxol alone, and the number of patients who received more 
than 6 cycles of chemotherapy was increased by 9 percent. 
	[Slide]
	I just want to comment here briefly that there is 
some evidence that there is a paclitaxel-Herceptin drug 
interaction in that the serum concentration of Herceptin is 
increased in patients who received paclitaxel compared to 
Herceptin patients from alternate studies who received 
Herceptin alone.  This is associated with decreased 
clearance.  This was seen in the preclinical studies in 
monkeys and seen in humans in the clinical study.
	[Slide]
	We also looked at the data in terms of why 
patients chose to stop therapy, and one element that stood 
out was adverse event as a reason in patients in the 
AC-Herceptin arm, 17 percent compared to 1 percent of 
patients in the AC arm, and also slightly increased in the 
paclitaxel-Herceptin arm versus Taxol.  Discontinuation of 
therapy on this slide refers to discontinuation of 
Herceptin, discontinuation of Herceptin and the 
chemotherapy, or discontinuation of the chemotherapy.
	[Slide]
	On this slide we looked at discontinuation of 
Herceptin independent of chemotherapy, which is why we don't 
have the 2 control arms here.  We see that adverse events 
still stand out as an imbalance between the AC-Herceptin 
compared to the paclitaxel-Herceptin group. 
	[Slide]
	The FDA analysis of the efficacy endpoints 
consisted of a review of every case report form, the adverse 
events, and incorporating standard oncology practice.
	[Slide]
	This is basically the curve that you already saw, 
and it is the Kaplan-Meier estimate of time to progression 
in all patients.  The yellow line -- and, actually, the 
color choice was independent of the sponsor; we both think 
the same on this -- the yellow line is the Herceptin 
patients and the green line is the chemotherapy alone 
patients.  What you see is that the curves separate early 
and continue to stay separate throughout, and that there is 
fairly complete data in that the curves go almost to 
because, particularly the control curve.
	[Slide]
	And, pulling out the AC patients, we still see 
significance with a p value of less than 0.001.
	[Slide]
	Pulling out the paclitaxel patients, the effect is 
more impressive. 
	[Slide]
	The specific numbers for median time to 
progression for the Herceptin plus chemotherapy group, we 
determined at 7.3 months compared to chemotherapy alone at 
4.5 months. 
	[Slide]
	Looking at the subgroups, there was an improvement 
in the AC arms by 2.1 months and for the paclitaxel arms 4.2 
months improvement in median time to progression.
	[Slide]
	The secondary efficacy points that I will discuss 
are overall response rate, duration of response, and 
survival.
	[Slide]
	Again, in determining response rate we looked at 
all the case report forms and additional data that the 
sponsor submitted on their analysis of 69 patients who 
hadn't been seen by the REC.  We found that in the 
Herceptin-chemotherapy arm the response rate was 43 percent, 
and in the chemotherapy alone arm 29 percent, with a p value 
of 0.001.
	[Slide]
	Looking at the subgroups, the difference was more 
striking for the Taxol-Herceptin compared to Herceptin alone 
subgroup.
	[Slide]
	Median duration of response for the Herceptin plus 
chemotherapy group was 9.3 months, and for chemotherapy 
alone 5.9 months, so improvement there as well.
	[Slide]
	Here we see that the improvement is carried 
through within the subgroups. 
	[Slide]
	Looking at the survival of all patients treated in 
the pivotal study, we have to keep in mind that the data 
after a year are immature and it is difficult to come to 
conclusions about median overall survival.  If we look at 
this curve, we would determine that it is the same because 
the curves come together.  If you look at 1-year estimates, 
they are separate for a period of time prior to coming 
together but, again, it is very difficult to come to any 
conclusions because of the immaturity of the data.
	[Slide]
	This is what the curves look like for the AC 
patients. 
	[Slide]
	And, for the paclitaxel patients actually the 
curves do remain separate.
	[Slide]
	So, in summary for the Phase 3 study, there is an 
improvement in time to progression for patients on the 
Herceptin arm, both overall, 2.8 months, and in the 
subgroups, 2.1 months for AC-Herceptin and 4.2 months for 
Taxol-Herceptin.
	[Slide]
	The response rate of patients treated with 
paclitaxel was significantly improved by the addition of 
Herceptin.  The response rate of patients treated with AC 
was not significantly improved by the addition to AC.  
However, the absolute difference trended in favor of the 
Herceptin arm.
	[Slide]
	The ability to make conclusions about the median 
overall survival is limited because the data are not mature 
at this time.  The 1-year overall survival is improved in 
the Herceptin arm, both overall and in the subgroups. 
	[Slide]
	The treatment effect was greater in patients 
enrolled and treated in the paclitaxel subgroups than in the 
AC subgroups.
	[Slide]
	Now I want to go on and look at the efficacy 
endpoints in light of patients baseline assessment for level 
of HER2/neu protein overexpression, 2+ and 3+.
	[Slide]
	As I mentioned already, the initial antibody used 
for screening was 4D5 which is the parent antibody to 
Herceptin.  It binds to the extracellular domain of the HER2 
receptor.  They subsequently added the use of antibody CB11 
which binds to the intracellular domain of the receptor.  
The PMA filed for test kit is a polyclonal antibody.  It is 
neither of these antibodies, and it binds to the 
intracellular domain. 
	The indication that they are seeking for the test 
kit is for the selection of patients to treat with 
Herceptin.  The assessment of the immunohistochemistry is 
semi-qualitative on a scale of 0-3, where patients who are 
2+ and 3+ are determined as positives.  In the test kit 
filed with the Center for Devices for licensing -- I just 
want to mention briefly that there are patients with that 
kit who tested as 2+ who would have tested negative by the 
concordance study in the pivotal study.  That is a point I 
just want you to keep in mind.
	[Slide]
	This is the distribution of HER2 positivity by 
level of expression and, as you can see, it is very 
consistent.  A quarter of patients were 2+, three-quarters 
of patients were 3+.
	[Slide]
	We looked at response rate by level of expression, 
and what we found in the Phase 2 study with Herceptin as a 
single agent is that there were more responders 
percentage-wise in the 3+ group than in the 2+ group, 17 
percent versus 4 percent. 
	[Slide]
	We then looked at response rates in the Phase 3 
pivotal study, and we saw a similar effect where the 
patients on the Herceptin-chemotherapy arm who were 2+ 
overexpressors had a response rate of 32 percent, which was 
the same as the response rate on the chemotherapy alone arm 
of 33 percent.  But when we look at 3+ overexpressors, there 
is a significant increase, 47 percent versus 27 percent. 
	[Slide]
	We then looked at the data of the pivotal study in 
terms of median time to progression, and we looked at 2+ 
patients versus 3+ patients.  I think you can see here that 
for the 2+ patients, whose data are shown on this slide, the 
curves overlap, with a p value of 0.56. 
	[Slide]
	On this slide are the 3+ patients, and this curve 
is more reminiscent of the treatment effect that you saw 
earlier in the slides that I showed for the pivotal study, 
not separated out by 2+ and 3+, such that the curves 
separate early and remain separate throughout. 
	[Slide]
	If we can go back to the previous slide, if we 
take the difference between these 2 curves --
	[Slide]
	-- and we compare it to the difference in these 
curves, there is an interaction, and that is significant as 
well, with a p value of less than 0.05.
	[Slide]
	Again, we did the same thing with survival.  This 
is the survival plot for the 2+ patients. 
	[Slide]
	And, this is the survival plot for the 3+ 
patients. 
	[Slide]
	So, in summary of the immunohistochemistry data, 
there is a higher response rate among 3+ patients as 
compared to 2+ patients treated with Herceptin alone as 
second- or third-line therapy.  Patients with tumor scored 
as 3+ had higher response rates when Herceptin added to 
chemotherapy compared to patients with tumors scored as 2+.
	[Slide]
	The addition of Herceptin to chemotherapy improved 
the median time to progression by 4.1 months, and improved 
survival among 3+ patients.  The addition of Herceptin to 
chemotherapy did not improve median time to progression or 
survival for 2+ patients.  There is a significant 
interaction between the level of overexpression and the 
effect of Herceptin on time to progression. 
	[Slide]
	Now I want to turn to the safety data, and I will 
be dealing with the Phase 2 and Phase 3 studies together.
	[Slide]
	We will look at Herceptin as a single agent, 
Herceptin in combination with paclitaxel, and Herceptin in 
combination with anthracycline plus cyclophosphamide. 
	[Slide]
	You have already heard a considerable amount about 
the infusional toxicity.  We are in complete agreement with 
the sponsor's assessment.  Nearly half the patients 
experienced one form or another of this toxicity.  It 
primarily occurs with the first infusion.  Patients 
experienced chills, fever, pain, sometimes pain at the site 
of the tumor, asthenia, nausea, vomiting and headache.  
Rarely hypotension occurred.  These symptoms are 
self-limited and easily treated with standard medications.
	[Slide]
	Now I want to turn to the cardiotoxicity issue.  
We analyzed the data basically the same way that the 
sponsor's cardiac response evaluation committee did, using 
the same criteria of New York Heart Association 
classification and ejection fraction.  However, we looked at 
the patient's worst status in our analysis.
	[Slide]
	This is a summary of the incidence of 
cardiotoxicity in the subgroups of the pivotal study, and 
the last column is the Phase 2 study of Herceptin alone.  
The black shaded area is patients who experienced class III 
or class IV events, and the red shaded area is patients with 
less severe events, class I and class II.  The sum of the 2 
is the total percentage in each group. 
	For the AC-Herceptin group, the percentage is 28 
percent; for AC alone, 7 percent; for Taxol-Herceptin, 11 
percent; for Taxol alone, 1 percent.  The Taxol alone 
patient, I just want to note, actually had staphylococcal 
endocarditis, and her ejection fraction was 71 percent, but 
we did include her because she did have a severe cardiac 
event. 
	The events that occurred in the AC-Herceptin arm 
in general were more severe than those that occurred in the 
AC arm.  As you have already heard, some patients did 
require dopamine, dibutamine.  One patient actually 
developed left ventricular dilatation, developed a thrombus 
to her brain, and was left aphasic and, I believe, 
hemiplegic.
6:00 pm		[Slide]
	The paclitaxel-Herceptin arm, if you compare it to paclitaxel alone, 
also has a considerable increase in the number of cardiac 
events though, as far as severity, they tended not to be as 
severe as those in the AC-Herceptin arm.  We did see 
cardiotoxicity when Herceptin was administered alone, 
although this was in a group of much sicker patients.  All 
but 2 of them had received prior anthracycline therapy but 
those 2 patients had significant cardiac disease at 
enrollment.  So, it is difficult to sort out that data. 
	[Slide]
	We were trying to look at the events in terms of cumulative 
anthracycline dose received by the patients, and we divided 
it into those who had received less than 300 mg/m2 and those 
who had received 300-450 mg/m2, which actually would be the 
majority of patients, and those who received higher doses, 
above 450 mg/m2.  At the lowest dose group we saw 12 percent 
incidence overall of class III and IV events compared to AC 
alone where we saw none.  In the mid range we saw 25 percent 
when Herceptin wa added to AC compared to 3 percent with AC 
alone.  In the higher dose levels there was a smaller 
difference, 27 percent versus 20 percent. 
	[Slide]
	Actually, the sponsor did this analysis too in their submission, and 
we also did the same analysis.  This is comparing the 
cumulative anthracycline dose to the proportion of cardiac 
events in the population overall.  I think most oncologists 
are used to seeing these curves.  The yellow is the 
Herceptin group and the green is the control.  These are 
only the AC patients.  These do not include Taxol patients. 
	As you can see, if you look in the vertical dimension, there are 
marked differences even at the lower doses.  At the doses at 
which you would see most patients treated, the minimum 
number of cycles of this barring toxicity was 6 cycles, 
which was 360 mg/m2, which falls right about here.  Some 
patients continued to receive more than that.  So, do see 
this sharp increase. 
	Now, the data further out -- these are much fewer patients who 
received higher doses, but the point of this is that the 
curve is shifted to the left for the Herceptin group. 
	[Slide]
	We assessed death due to cardiotoxicity as 2 occurring in the 
AC-Herceptin arm and 2 in the AC alone arm; none in the 
Taxol subgroups.  This could have been death due to 
cardiotoxicity and breast cancer but, as was mentioned 
already, it is sometimes difficult to differentiate the two 
and sort it out, but we certainly felt that the 
cardiotoxicity contributed significantly to the death of 
those patients.  One of the AC patients died after she 
crossed over to the extension study and received Herceptin.
	[Slide]
	We also looked at past medical history for cardiac disease, prior 
radiation therapy to the chest, age and we really found no 
factor that was significantly associated but certainly all 
could play a contributory role.  It is simply difficult to 
tell because we don't have enough data to say.  Dexrazoxane, 
as you know, was administered to some patients but did not 
appear to prevent cardiotoxicity. 
	[Slide]
	Now I want to move on to hematologic toxicity.  In evaluating the data 
that was submitted, the adverse event listings do list 
leukopenia, neutropenia, and anemia as events.  However, 
some patients, if you looked on their medication listing, 
may have received blood transfusions but not have been 
recorded as being anemic, or required G-CSF or GM-CSF but 
not necessarily listed as neutropenic. 
	So, when we analyzed the data we did a composite, such that we looked 
at leukopenia related events and anemia related events.  For 
the leukopenia related events we looked at leukopenia or 
neutropenia, making sure not to count patients double if 
they had both recorded; use of G-CSF or GM-CSF; and 
incidence of febrile neutropenia or neutropenic sepsis.
	For the anemia related events we looked at any recordings of anemia, 
use of erythropoietin and any blood transfusions that were 
administered.  A blood transfusion event was counted as one 
event no matter how many units were administered.
	[Slide]
	What we see here is that in the AC-Herceptin group the incidence of 
leukopenia related events was 67 percent compared to 46 
percent in the AC group.  It was also increased with the 
Taxol subgroups, 32 percent in Taxol-Herceptin versus 24 
percent. 
	For anemia related events there were also increases, not so great but 
still present in the AC-Herceptin compared to AC and 
Taxol-Herceptin compared to Taxol alone. 
	[Slide]
	We also noticed that gastrointestinal toxicity was increased in the 
patients who received Herceptin and chemotherapy compared to 
chemotherapy alone.  Here you can see that diarrhea is 
almost doubled in the AC patients and in the Taxol patients.  
If you look at patients who received Herceptin alone prior 
to crossing over within that study after the progressed, the 
incidence was 27 percent.  Similarly, with abdominal pain we 
see increases in the Herceptin groups.
	[Slide]
	There were increases in the incidence of infection, 46 percent in the 
Herceptin plus chemotherapy group versus 30 percent in the 
chemotherapy alone group.  The incidence in the single-agent 
study was 20 percent. 
	Neurotoxicity incidence was increased in the Taxol-Herceptin group but 
our analysis reveals that this is most likely related to the 
fact that these patients received considerably more Taxol, 
but there was an increased incidence of paresthsias, 
peripheral neuritis and neuropathy.  We can't necessarily 
attribute that to the Herceptin.
	[Slide]
	So, in summary of the safety data, Herceptin alone produces an 
infusional toxicity, cardiac toxicity and GI toxicity.  
Herceptin plus chemotherapy also results in infusional 
toxicity and increases of cardiac, gastrointestinal, 
hematologic and infectious toxicities.
	[Slide]
	Now I am going to present my conclusions overall.
	[Slide]
	Conclusion number one, Herceptin is active as a single agent in 
patients with metastatic breast cancer who have progressed 
following one or more prior chemotherapy regimens for 
metastatic disease. 
	[Slide]
	Tumor responses can be durable, with a median duration of 9 months, 
and are seen in visceral, soft tissue and bone metastases.
	[Slide]
	Patients with tumors scored as 3+ in the Phase 3 study have a higher 
tumor response rate than those scored as 2+. 
	[Slide]
	When administered as first-line therapy in combination with AC or 
paclitaxel chemotherapy regimens, Herceptin improves median 
time to progression by 2.8 months overall compared to 
patients receiving chemotherapy alone.
	[Slide]
	A greater clinical benefit is observed by the addition of Herceptin to 
paclitaxel than is observed by the addition of Herceptin to 
AC chemotherapy.
	[Slide]
	In an exploratory analysis, clinical benefit from the addition of 
Herceptin to chemotherapy was limited to patients with 
tumors scored as 3+, as opposed to 2+, for overexpression of 
HER2/neu protein by immunohistochemistry.  Patients who were 
3+ had improved time to progression, improved response rates 
and improved survival.
	[Slide]
	The 1-year overall survival is improved in the Herceptin plus 
chemotherapy arm, however, the data are not mature enough to 
assess the median survival at this time. 
	[Slide]
	Moving on to safety conclusions, Herceptin commonly produces an 
infusional toxicity which is self-limited.
	[Slide]
	The addition of Herceptin to AC or to paclitaxel chemotherapy results 
in a marked increase in the incidence of cardiotoxicity.
	[Slide]
	Cardiotoxicity is frequent and severe in patients receiving AC plus 
Herceptin.
	[Slide]
	The incidence of hematologic and infectious toxicity is increased when 
Herceptin is added to AC or paclitaxel.
	[Slide]
	Herceptin produces gastrointestinal toxicity whether administered 
alone or in combination with AC or paclitaxel.
	[Slide]
	For the last few conclusions, these address some limitations of the 
development program.  Only one schedule of Herceptin 
administration has been studied.  It is not known if a 
shorter duration of therapy is equally beneficial or 
provides an improved safety profile.  Basically, on both 
studies patients received Herceptin from the time of 
enrollment until progressive disease.  No other schedules 
have been studied.
	[Slide]
	The combination of Herceptin with antineoplastic agents other than AC 
and paclitaxel is primarily anecdotal.  It is not possible 
to make conclusions regarding the efficacy or safety of such 
combinations at this time.
	[Slide]
	Because the baseline demographics of the patients treated with 
paclitaxel are markedly different from those treated with AC 
in the pivotal study, it is impossible to make conclusions 
regarding the use of Taxol-Herceptin compared to AC alone as 
first-line therapy for metastatic breast cancer.
	[Slide]
	To pull together the limitations, only one dosing schedule has been 
tested.  These are not studies to determine what is optimal 
first-line therapy for metastatic breast cancer, other than 
in those subgroups studied within the context of the 
protocols presented today.  Selection characteristics of 
patients who will benefit from Herceptin, comparing 2+ to 3+ 
patients, is limited by the fact that this wasn't 
prospectively designed into the study, but certainly 
exploratory analyses are significant.  Finally, the 
assessment of cardiotoxicity is limited by the manner in 
which the data was collected. 
	That completes my presentation.
	DR. DUTCHER:  Thank you.  Before we entertain questions, could you and 
perhaps Dr. O'Leary just comment on what the issues are with 
the test kit, because I don't think the members of the 
committee are really aware of the issues in terms of who got 
tested with what.
	DR. JERIAN:  The PMA for the test kit -- first of all, let me just say 
that the antibody used in the test kit, as I mentioned, is a 
different antibody but because there are not samples 
available from the clinical study to test that antibody a 
concordance study was done with the polyclonal antibody.  
The tissues obtained for that concordance study were from a 
registry, NCI registry I believe, tissue bank.  Without 
getting into too much of the detail of the PMA because that 
will be dealt with on Friday, the concordance study showed 
fairly good concordance, although there were these 
differences in patients who were scored as 2+ by the 
polyclonal kit, the DAKO kit.  Many of those were not scored 
as positive by the studies used to identify patients for 
this study. 
	DR. O'LEARY:  So, basically, then the PMA that we will be looking at 
on Friday does not bear a direct relationship to the 
survival information being presented today, but that this is 
an extrapolation use of sort of a surrogate so that a 
question that is relevant to that and to this -- you said 
that there were two antibodies used in the study 4D5 and 
CB11.  One of these two antibodies would appear likely 
possibly to be more closely related in terms of the epitope 
target than the other to the test kit antibody.  Is there a 
matrix that could be put up to show in any of these tumors 
that might have been assessed using both antibodies, both 
4D5 and CB11, a concordance between those two antibodies in 
the same laboratory?
	DR. JERIAN:  We attempted to look at that actually, and one limitation 
we have in doing that analysis is that there are far fewer 
patients who had the CB11 antibody test done.  I hesitate 
putting that data up at this point.
	DR. O'LEARY:  Can you give us some idea of what the proportion was, 
what fraction used the 4D5 and how many used the CB11, and 
how many had both?
	DR. JERIAN:  I am sorry, I don't have the numbers with me right now.
Questions from the Committee
	DR. DUTCHER:  Questions for FDA from the 
committee?  Dr. Margolin?
	DR. MARGOLIN:  Just a very tiny question.  When 
you looked at the potential for imbalance in terms of the 
randomization in the two groups, there were usual factors, 
but did you look at the use of eridia?  In bone-only 
patients use of eridia might potentially alter the time to 
detection of progression since that was one of the primary 
endpoints?
	DR. JERIAN:  No, we didn't do that evaluation, but 
I think that is a good point. 
	DR. DUTCHER:  Dr. Schilsky?
	DR. SCHILSKY:  A couple of questions.  I think the 
points you bring out about the differences in response with 
respect to intensity of staining are critical in helping to 
frame a risk-benefit assessment, and I wonder if there is 
any data from this study that helps to provide some ability, 
just to have a sense of what the concordance rates are among 
people who look at these slides.  I don't do this but I 
don't have any idea, for example, how difficult or easy it 
is to discriminate 3+ from 2+ staining.  You know, all of 
this was done in a central reference laboratory but one 
might ask if you took, you know, five pathologists and had 
them look at all of the same material what would be the 
agreement with respect to what is 3+ and what is 2+, just 
using the antibody that was used in the study.
	DR. JERIAN:  Understood.  As you know, with 
immunohistochemistry staining, it can be very subjective 
and, in fact, for the PMA kit there are standards submitted 
for the 3+, the 1+ and the 0, but none for the 2+, and 2+ 
patients are difficult to determine; 1+ are difficult to 
determine; 3+ are quite apparent and 0 is quite apparent.  
But it is very difficult to know what to do with the 2+ and 
what to do with the 1+, and who actually is falling into 
which group.
	DR. SCHILSKY:  That strikes me as being 
particularly important for a patient who might, you know, be 
appropriate for AC with Herceptin and who has a 2+ tumor.  
She would be exposed to lots of risk for toxicity and not 
much benefit. 
	I have one other question for you about the 
toxicity.  You mentioned that in the Phase 2 study patients 
who progressed had several options, one of which was to 
continue to receive Herceptin at twice the dose that they 
had been receiving previously.  I am wondering how many 
patients actually did that, and whether that sheds any light 
about dose-response relationships and risk of cardiac 
toxicity.
	DR. JERIAN:  A lot of those data are, you know, 
anecdotal.  Patients could receive a variety of regimens.  
They may have received tamoxifen and Herceptin, 5FU and 
Herceptin, CMF and Herceptin.  It is very difficult to come 
to any conclusion from that data regarding efficacy.
	DR. DUTCHER:  Dr. Simon?
	DR. SIMON:  Am I correct in saying we don't really 
have information about whether Herceptin alters the 
pharmacokinetics of Taxol or Adriamycin or cyclophosphamide?
	DR. JERIAN:  I am sorry, I didn't hear the last 
part.
	DR. SIMON:  We know about the effect of Herceptin 
on the pharmacokinetics of the chemotherapy drugs used?
	DR. JERIAN:  Well, as I mentioned, we may know 
something about what it does to the Herceptin concentration.  
It doesn't affect Taxol levels in the preclinical studies, 
but those were not assessed in the pivotal study, and AC 
levels were not assessed in the pivotal study.  So, we don't 
know what it does --
	DR. SIMON:  But preclinically there was no 
indication?
	DR. JERIAN:  Preclinically there was no indication 
of an effect on the chemotherapy agents. 
	DR. DUTCHER:  Yes, Dr. Weiss?
	DR. WEISS:  Based on your look at the 
cardiotoxicity data, do you have any thoughts as to when, 
how or whether patients who were candidates for this agent 
should be screened in any way prior to therapy, particularly 
if the indication ever broadens to people without metastatic 
disease?  Is there something that a physician should be 
doing before --
	DR. JERIAN:  That is one of the questions we have 
for you!
	[Laughter]
	DR. WEISS:  I was hoping you would answer it.
	DR. JERIAN:  You know, it is very difficult to 
say.  Actually, I will commend the sponsor for going back 
and trying to get the because information on these patients, 
and without that comparison it is difficult to say.  
Certainly, monitoring needs to be in place on some level. 
	DR. DUTCHER:  Was it being done in the open label?
	DR. JERIAN:  It is being done now. 
	DR. DUTCHER:  Dr. Simon?
	DR. SIMON:  I just wanted to clarify whether I 
heard your answer to Dr. Schilsky's question before.  Did 
you say with the kit that is coming up for review on Friday 
the determination of who is 3+ is straightforward?
	DR. JERIAN:  It is rather straightforward, yes.
	DR. SEIGEL:  We probably have a concordance table.  
I think what you are trying to point out is that there is 
pretty high concordance at the 3+ level, and when you get to 
the 2+ a significantly large number of them are 0 or 1+.  
Some are 3+; some are 2+.  Do you have that?
	[Slide]
	DR. JERIAN:  This is actually going to be 
presented by the FDA at the CDRH meeting.  This is a 
concordance table, and 3, 2, 1 0 refer to the 
immunohistochemistry score.  At the top you have the assay 
used and the clinical study.  A slide could either be 
positive with CB11 or 4D5.  On the other axis you have the 
DAKO assay.  If you look at the two italics numbers, those 
are patients whose scores are 2+ by the DAKO assay but were 
negative by the core laboratory clinical trial assay. 
	DR. SEIGEL:  The reason that we emphasize that 
second line in a couple of comments as developed in one of 
the questions that we might ultimately get to tonight, is 
that we can present the clinical data, of course, regarding 
the first two columns -- response rates, if you were 3+ or 
2+, and the relatively weaker evidence of benefit in 2+ 
patients, but we will not be able to write an indication for 
those columns because that test is not developed throughout.  
We can only write indications for the patients in the row, 
and if one were to look at that 2+ row, you would have to 
recognize that that includes a lot of patients who would 
have been in the trial, but also a lot who would not have 
been in the trial. 
	DR. JERIAN:  I just also want to point out that 
one of the reasons they brought forth the polyclonal kit is 
that the other immunohistochemistry stains required 
multiple, multiple steps and were very cumbersome to employ, 
and the polyclonal kit apparently is less cumbersome in 
methodology. 
	DR. SIMON:  Do I understand the other part to Dr. 
Schilsky's question, that you don't really have inter-lab 
reproducibility data?
	DR. JERIAN:  I am sorry?
	DR. SIMON:  You don't have inter-lab 
reproducibility data?
	DR. JERIAN:  They looked at inter-reader 
variability.  They they did assess all those points but I 
don't have those data for you. 
	DR. DUTCHER:  Yes?
	MS. ZOOK-FISCHLER:  As a patient rep, I am very 
excited about the potential that Herceptin appears to 
present, but it seems to me that the patient population was 
a very sick population whose quality of life is already 
quite compromised.  Then I am hearing all of the potential 
toxicities in addition to the cardiotoxicities.  I wonder 
whether there has been consideration of studying Herceptin 
on women who are not quite so sick, or to limit it only to 
women if they are that sick if they are overexpressing 3+.
	DR. JERIAN:  Yes, understood.  I think the sponsor 
certainly is planning on pursuing other studies.  I think 
that is quite an active area of consideration but we haven't 
received any other, you know, complete studies, other than 
what I have shown you today. 
	DR. LIPSCHULTZ:  I just have a couple of 
questions.  One of your slides -- I just want to see if I 
understand it correctly.  We were looking at the incidence 
of grade III and IV cardiac disease, in other words, 
symptomatic left ventricular dysfunction, presumably.  I 
think I saw there that in the 301-450 group it was 25 
percent in the Herceptin and AC group.  Am I understanding 
that correctly, that 25 percent of patients on that regimen 
in the 301-450 cumulative anthracycline dose had symptomatic 
left ventricular dysfunction or congestive heart failure?
	DR. JERIAN:  Right.  That is of the total patients 
treated at that dose. 
	DR. LIPSCHULTZ:  Right, okay.  I saw in the 
original protocol that ejection fractions of 45 percent or 
above were acceptable for inclusion in the study.  
Oftentimes people think 45-55 as being somewhat depressed.  
Do you have a feel for that, those that had baseline, were 
any in that range when you reviewed the data?
	DR. JERIAN:  When we looked at the baseline 
ejection fraction data that was provided for the patients 
who had cardiotoxicity, again, a lot of that was missing for 
the patients who didn't experience cardiotoxicity, and I 
don't see any major differences between the subgroups of 
patients who had cardiotoxicity.  I think the mean was 
around 60 percent, or something like that. 
	DR. LIPSCHULTZ:  When you reviewed the data, in 
the last 20 months or so, whatever, since cardiac problems 
became apparent, was there an increased number that had 
ejection fractions or other cardiac parameters -- I am just 
trying to get a feel for this.  You know, when I look at 
that and see that for the Herceptin-AC patients only 50/143 
had baseline, I am trying to get a feel for who these 
patients are.  Are these only the ones that had heart 
failure?  I guess the thing is that when I look at a rate of 
25 percent and I know that in the AC group you have 3 
percent, and in FAC regimens this is a factor of 10 higher, 
you know, this is an enormous amount of symptomatic heart 
disease.  I am just trying to get a feel for it.  It seems 
that this may be a minimum for combined 
asymptomatic-symptomatic LV dysfunction.  I am trying to get 
a feel for who these patients are that you actually have 
data on, or they have data on. 
	DR. JERIAN:  Not all patients were symptomatic.  
Well, if they were III or IV they were symptomatic, but 
there were some class I patients who were monitored by their 
investigator, I assume, because they had a cumulative 
anthracycline dose so that that investigator typically would 
check the ejection fraction at that time point, and they 
were evaluated and found to have a decreased ejection 
fraction.  That would be the practice of many oncologists.  
But that practice did vary depending on the investigator and 
the geographic region.  There was one site in Germany where 
they looked at fractional shortening instead of ejection 
fraction.  So, that is another factor that makes this 
analysis difficult.  It was very investigator dependent, and 
you had to look at each individual patient as a unit of one 
because one investigator would be more aggressive and the 
next one may not be more aggressive in checking ejection 
fractions in the absence of symptoms.
	DR. SCHILSKY:  As I understand it, this was a set 
of samples from a registry, not from the patients in this 
trial.  Right?  And the clinical trial assay was performed 
and the DAKO assay, which is the one that is proposed to be 
used in the future, was performed.  So, there are 126 
specimens that were 2+ by the DAKO assay and, of those, 16 
would have been 3+ by the clinical trial assay.  Right?
	DR. JERIAN:  That is right. 
	DR. SCHILSKY:  So if, for example, a decision were 
made to exclude from therapy with Herceptin all patients who 
score 2+, then potentially 16/126 patients might be excluded 
who might otherwise have benefitted because they were 
actually 3+ using the assay done in the study.
	DR. JERIAN:  That is right.  It is very difficult 
to know what to do.  I will comment on this data.  The ratio 
of 2+ and 3+ slides was 50-50, and then they extrapolated 
that to what a normal population would be, which is 25-75. 
	DR. SEIGEL:  Yes, let me just pursue that point.  
If you are looking at fractions of that 126, you should 
recognize that these were not all specimens from all 
patients in the registry that would have been eligible for 
the trial.  They specifically selected for having a higher 
proportion of samples that were positive to give this 50-50 
ratio.
	DR. SCHILSKY:  What I am struggling with I think 
is that, you know, since the assay isn't perfect, and if the 
data are true that the only patients who benefit are those 
who are 3+ in their staining, and since the toxicity risk, 
at least with AC, is substantial, if one arbitrarily decided 
to only offer this therapy to patients with specimens with 
3+, then who might be left out who could potentially benefit 
just based upon variability in the assay?  That is the hard 
part. 
	DR. DUTCHER:  Dr. O'Leary?
	DR. O'LEARY:  Yes, I wanted to get back to that.  
Can one renormalize this in some way to what the proportion 
would have been in the trial population?  Because the piece 
of this that doesn't come out clearly, at least to me, is if 
you make a cut-off at 3+ on the DAKO assay, and we assume 
that the DAKO assay is perfect, then what proportion of 
folks that would have benefitted or would have potentially 
benefited would we miss?  Alternatively, if the cut point 
were made at 2+, what percentage are potentially included 
that should not have been included when one looks at this in 
terms of the distribution of staining in the real population 
as opposed to something skewed to look at the concordance 
with a higher proportion of positive tumors? 
	DR. JERIAN:  I am sorry --
	DR. O'LEARY:  Well, the initial look is if you 
were to assume -- it would appear that around -- if you use 
the 2+ cut-off, about 40 percent of the folks that would be 
included as eligible for therapy would be folks that would 
be negative, 0 or 1+ by the lab core assay.  Alternatively, 
if you just include 3+ it looks like you lose about a third 
of the patients that would have been eligible for the lab 
core assay.  I think that is actually probably preserved in 
the sense that the 0s and 1s isolate pretty well. 
	DR. DUTCHER:  Dr. Margolin?
	DR. MARGOLIN:  My questions are biological and may 
be best directed at Dr. Slamon.  We have to decide whether 
to approve this, with all sorts of caveats about the safety 
of combining the drug.  But, we learned that there seems to 
be some interaction between expression or amplification of 
HER2 and response to Adriamycin without Herceptin.  We also 
learned from this month in JCO that there might be some 
important interactions with cisplatinum and HER2/neu in the 
antibody. 
	So, I guess the question is would the scenario be 
that in patients who are overexpressors when one gives some 
Adriamycin as part of their therapy and then, as soon as 
they fail, you give them either Taxol plus Herceptin, or 
platinum plus Herceptin, or Taxol plus platinum and 
Herceptin and at that point avoid the Adriamycin even if the 
time to relapse is long? 
	DR. SLAMON:  I think that you are right on the 
money with some of the questions you are asking.  The 
Adriamycin interaction is real, I think, based on the data 
that everybody has been showing, and the company was very, 
very up front with the investigators and was on top of it 
all along when it first started to happen.  But I don't 
think anyone has been saying that it can't be used 
absolutely with anthracycline, it just needs to be used with 
caution.  I mean, the only thing I wanted to get out into 
this discussion is, remember, I mean, those cardiac events 
are real but HER2 overexpressing breast cancer in the 
metastatic setting is a very deadly disease and it needs to 
be weighed in that context. 
	Now, can you use Adriamycin with the antibody?  I 
think the answer is yes.  I think it should be used 
cautiously, as the recommendation, as I understood it, was 
alluding.  Are there better combinations?  I think the 
answer is very possibly yes, and that is something that the 
sponsor is beginning to evaluate now.  Should you use 
Adriamycin?  Do we always have to use Adriamycin?  I think 
that is something that we are not going to get out of this 
trial.  Why is it the eleventh commandment that everyone 
with breast cancer has to be treated with Adriamycin?
	DR. MARGOLIN:  Well, maybe also you don't need the 
Herceptin with Adriamycin.  Maybe you need it with the other 
drugs to get the interaction but with Adriamycin you already 
have that interaction. 
	DR. SLAMON:  While I absolutely agree with that, I 
would still be somewhat concerned about the toxicity we are 
seeing, even delayed, in patients who have had prior 
anthracyclines.  So, I think the phenomena are real.  I 
think the drug can be used with anthracycline but with 
caution.  I also think, without any hard data yet except for 
the sort of interesting data in JCL, that there may be 
better combinations, and better combinations up front. 
Open Public Hearing
	DR. DUTCHER:  If there are no further questions 
for FDA, I think we should move along.  We do still have 
five more minutes of open public hearing.  Is Mr. Erwin 
here?  Could you please identify yourself and your 
associations, as well as your financial support?
	MR. ERWIN:   Sure. 
	I am Robert Erwin.  Thank you for agreeing to my 
request to speak after the data was presented.  I have no 
financial interest in Genentech.  I am Chairman of the State 
of California Breast Cancer Research Council, which spends 
about 10-15 million a year in cigarette tax money on breast 
cancer research.  I work for a small private biotech company 
which neither collaborates with nor competes with Genentech.
	I am here today, representing the Marti Nelson 
Cancer Research Foundation, and the cancer patients that we 
assist to enroll in clinical trials to obtain access to 
experimental medicine to evaluate off-label uses of drugs 
approved for other indications, and to assess the potential 
value of treatments unavailable in the United States.
	My wife, Marti, died of breast cancer in 1994 
after unsuccessfully attempting to gain access to the drug 
now known as Herceptin.  Since that time, Genentech has 
demonstrated its moral leadership in the biotechnology 
industry, and its compassion, by establishing an expanded 
access protocol for Herceptin, whereby as of now over 400 
women with advanced, HER2 overexpressing metastatic breast 
cancer have been able to obtain this drug in the realistic 
hope of extending life, or at least improving its quality.
	 Although a scientist might not call these cases 
significant and refer to them as anecdotal, the benefit 
experienced by each individual who was helped by this 
protocol was as clinically real as the benefit experienced 
by any individual in the pivotal studies. 
	The data presented today, in my opinion, speak 
clearly, and there is no doubt that this drug should not 
only be approved, but should become a part of the standard 
of care for HER2-overexpressing metastatic cancer.  The 
patient groups that we work with tend to be quite aggressive 
and we extrapolate aggressively from early stage data.  We 
would be very likely to recommend Herceptin plus Taxol over 
AC as first-line therapy for HER2-expressing metastatic 
breast cancer. 
	Two very important questions remain, however.  
One, why has it taken so long to get to this point when it 
was so clear to so many people in 1994 that this drug could 
extend life? 
	I believe that something is wrong with our 
institutional approach to providing effective treatment for 
cancer.  We are not talking about a healthy population in 
this regard but about people who are dying.  When every day 
counts we are losing years, as was illustrated in the early 
slide showing the regulatory time line going back to the 
completion of the Phase 2 study.  The fast track is not fast 
enough.  The sacred cows of the research funding process and 
the drug development and approval process are clogging up 
the road and, in the absence of data suggesting actual 
divinity, I think they need to be put back to pasture to 
enable innovative researchers and companies like Genentech 
to move more quickly, and move significant discoveries into 
general use. 
	Those of you in the FDA know which experimental 
drugs are working and which are not early enough to pull the 
promising candidates to the process proactively and rapidly, 
perhaps into pivotal Phase 2 studies.  You also know which 
combinations of as yet unapproved biologics have rational 
medical promise but are unlikely to be tested in combination 
for years to come. 
	How long do we have to wait to find out whether or 
not Herceptin in combination with Theratope, or some other 
proprietary biologic, can extend life beyond either alone?  
Under the current system, it will be well into the new 
millennium.  Why?  Disclosure of risk is essential, as is 
monitoring for unexpected toxicity.  Delays in access are 
fatal. 
	The second question is why is Genentech the only 
company to have an established practice of providing 
expanded access to promising cancer therapeutics?  Where are 
Chiron and Biomira and Janssen and Bristol-Myers and ImClone 
and Medarex, and all the other companies who plan to profit 
from cancer?  Those of you out there from the corporate 
world who sell Taxol and Adriamycin, and other 
chemotherapeutics, are selling products that usually benefit 
less than a third and harm 100 percent of your customers.  
People buy your products not because most of them benefit, 
but because all of them hope for benefit, and your profit is 
the same whether your customer lives or dies. 
	I believe that this truth carries with it a moral 
and ethical mandate to rethink the status quo and factor 
compassion into your operating practices, as Genentech has 
done.  And, it is not just the corporations who develop and 
sell oncologic drugs that share this obligation.  It doesn't 
really matter whether your currency of choice is the profit 
you might derive from the sale of marginally beneficial 
products or the tenure that you have derived from the 
tragically disappointing war on cancer.  Everyone whose 
profession exists because of the suffering of cancer 
patients has a moral obligation to step up to the line and 
deliver the best that science has to offer to people who 
need it the most as rapidly as possible.  This includes 
insurance companies, managed care organizations, and the FDA 
itself. 
	Herceptin may be the first drug for the treatment 
of metastatic breast cancer that actually helps more people 
than it harms, but I hope it won't be the last.  With this 
new generation of cancer drugs, expanded access is not only 
a matter of altruism.  Genentech has demonstrated that 
everyone can win from expanded access and from a close and 
constructive relationship between a company and the 
community of people most affected by cancer.  Genentech has 
also shown that expanded access is compatible with good 
science and good medicine. 
	I urge you to accept the challenge of Genentech's 
leadership and remember that each individual is more than an 
anecdote.  Each person is a valuable, loving, loved and 
irreplaceable individual.  Expanded access for all of the 
new generation of cancer therapeutics is what we need.  And, 
don't wait around until organizations like ours and the 
broader coalitions of cancer activists engage you in this 
issue.  Do it now because it is the right thing to do. 
	As Marti was dying, I promised her that her death 
would not be in vain.  I intend to keep that promise.  We 
have only made a very small start.  We are going to continue 
because it is the right thing to do.
	Thank you. 
Committee Discussion and Vote
	DR. DUTCHER:  Thank you very much. 
	We are now going to consider questions regarding 
this agent.  We have heard a lot of information. 
	First, we will try to go through in order, but I 
know that Dr. Weiss has to leave quickly and I want him here 
when we talk about the cardiotoxicity issues.  We will start 
with the first question and then we will see where we go. 
	The first question is -- you can't hear me?  Now 
you can hear me?  Okay.
	We are going to be going through the questions, as 
I said, except that if we get close to a certain time limit 
we want the cardiologists here to discuss it.  So we will 
jump ahead.  You have to leave at 7:30?  We will be done.  
We will be fine. 
	As a single agent, Herceptin produced objective 
tumor responses in 14 percent of patients studied in 
clinical trial H0649, with a median duration of 9.1 months.  
The patients in this study had all received one or more 
prior chemotherapy regimens with or without hormonal therapy 
for metastatic disease.  Responses were seen in a variety of 
metastatic sites including visceral, soft tissue and bone 
lesions.  Herceptin, when administered as a single agent, 
was associated with infusional toxicity commonly seen with 
other monoclonal antibody therapies: fever, chills, 
myalgias, back pain, tumor site pain, nausea, and flu-like 
symptoms.  This toxicity appeared to be self-limited and 
controlled with medications and/or with adjustments in the 
rate of the infusion.  Diarrhea (32 percent), abdominal 
pain, (27 percent), and stomatitis (10 percent) were 
commonly seen and may be related to the known binding 
characteristics of parent antibody of Herceptin, 4D5, to 
normal gut tissues.  Cardiotoxicity (7 percent) when 
observed was most commonly manifested as heart failure, with 
a decrease in the cardiac ejection fraction.  It was more 
often severe in nature and occurred in patients with and 
without prior anthracycline exposure; although, those 
without anthracycline exposure did have preexisting cardiac 
disease.  Anemia (10 percent) and leukopenia (8 percent) 
were noted in this heavily pretreated population. 
	So the questions are three.
	(a) Do the objective response data demonstrate 
efficacy of Herceptin as second- or third-line single-agent 
therapy of metastatic breast cancer?
	(b) Is the toxicity profile of Herceptin 
acceptable for use as a single agent in second- or 
third-line therapy of metastatic breast cancer?
	(c)  Does therapy with Herceptin as a single agent 
provide net clinical benefit for patients with metastatic 
breast cancer when used as second- or third-line therapy?
	So, who would like to take a stab at (a)? 
	DR. MILLER:  I think the trial did show objective 
evidence of efficacy in the Phase 2 trials.  So, they met 
the criteria put out by the trial. 
	DR. DUTCHER:  Any other comments?  And, in terms 
of the toxicity profile for use as a single agent in second 
or third line?  Any comments?  Dr. Doroshow?
	DR. DOROSHOW:  Let me take a stab.  I think that 
while the toxicity profile is acceptable, it is very 
important, I think, to point out to everyone here that the 
level of III and IV cardiac toxicity for Herceptin alone was 
greater than for AC. 
	And, while we may very much want to have this 
therapy available to us, it is really quite extraordinary, 
and I believe that there is probably a lot about the biology 
of this protein that we can learn with respect to this novel 
toxicity that the antibody alone produces and, hopefully, 
there will be a lot more study to make us understand that.
	In essence, we are saying that this protein 
produces a level of heart damage that is equivalent to 
Adriamycin alone, which is a pretty remarkable thing in and 
of itself, and the question really is the risk-benefit 
analysis. 
	DR. WEISS:  I would agree with that and I would 
add, as to question (b), that I would give an answer of yes, 
with the qualification that the committee consider 
recommending some pretreatment evaluation, cardiac 
evaluation of patients noninvasively in some way or other to 
help avoid a catastrophic cardiac complication whenever 
possible. 
	DR. DUTCHER:  For use of the antibody alone?
	DR. WEISS:  Yes.
	DR. DUTCHER:  Okay.  You know, we usually vote on 
each question, Jay.  So, I think what we will do is vote on 
each of these parts.  Is that what you want us to do?
	DR. SEIGEL:  I think if you discuss them all and 
vote on (c), I think that will work. 
	DR. DUTCHER:  Okay.  Any other comment on (b)? 
	[No response]
	On (c)?  Does therapy with Herceptin as a single 
agent provide net clinical benefit for patients with 
metastatic breast cancer when used as second- or third-line 
therapy?  Dr. Vose?
	DR. VOSE:  I think we have all heard today what a 
bad disease overexpression of HER2 breast cancer can be as 
far as the overall outlook, and I think relative to what the 
other options are for these patients, this is actually an 
excellent choice as long as we do make sure that we know 
that the baseline cardiac evaluation is done and that the 
physicians are aware of these possible toxicities, and that 
overall it does provide an excellent risk benefit. 
	DR. DUTCHER:  Any other comments? 
	[No response]
	All those who would vote yes on 1 (c), please 
raise your hand. 
	[Show of hands]
	Eleven, yes.  We have 12 votes, so it is 11 
voting.  So zero, no. 
	The next question is with respect to Herceptin in 
combination with chemotherapy, and particularly with 
paclitaxel. 
	Protocol H0648 tested the use of Herceptin with 
chemotherapy compared to chemotherapy alone as first-line 
therapy in patients with metastatic breast cancer.  
Chemotherapy consisted of an anthracycline, doxorubicin or 
epirubicin, plus cyclophosphamide or, in patients who had 
previously been treated with an anthracycline, paclitaxel.  
The groups receiving the two different chemotherapy regimens 
differed not only in prior therapy and study treatment but 
also in response rate, survival, and toxicity profile.  
Therefore, they are considered separately in questions 2 and 
3. 
	Question two, when compared to paclitaxel alone, 
Herceptin used in combination with paclitaxel chemotherapy, 
at 175 mg/m2 infused over 3 hours, was associated with a 
greater median time to progression by 4.2 months, and a 
higher 1-year survival rate, 61 percent versus 73 percent, 
but no significant difference in median survival.  The 
patients studied had not received chemotherapy for their 
metastatic disease, though they may have received hormonal 
therapy, and they had received prior anthracycline therapy 
in the adjuvant setting.  In addition, a few patients had 
received dose-intensive chemotherapy.  Herceptin in 
combination with paclitaxel was associated with infusional 
toxicity as noted above.  In patients receiving TH there was 
an observed 11 percent incidence of cardiotoxicity as 
compared with the 1 percent incidence in patients treated 
with Taxol alone.  The incidence of severe cardiotoxicity, 
class III or IV, was 4 percent for patients treated with 
Herceptin plus Taxol compared to 1 percent for patients 
receiving Taxol alone.  Other toxicities which appear to be 
increased when compared to patients receiving paclitaxel 
alone included: anemia, leukopenia, abdominal pain, 
diarrhea, vomiting, and infections. 
	(a) Do the data regarding time to progression and 
survival provide evidence of improved efficacy of the 
combination of Taxol-Herceptin over Taxol alone for the 
first-line treatment for metastatic breast cancer?
	Who would like to comment?  Dr. Schilsky?
	DR. SCHILSKY:  I would have to say unequivocally 
yes.  In fact, I think the data are quite striking and 
perhaps the greatest demonstration of clinical synergy that 
I have seen in any solid tumor therapy.  It is quite 
remarkable. 
	DR. DUTCHER:  (b) Given that only patients who had 
received prior anthracycline therapy were studied in these 
regimens, if approved, should the indication be limited to 
patients who have received prior anthracycline therapy?  Dr. 
Miller?
	DR. MILLER:  I don't think so.  I mean, we are 
concerned about the cardiotoxicity, and I don't think we 
should mandate that.  I mean, clearly this shows efficacy 
even in patients who have previously been treated with a 
very active drug.  So, I do not think it should be limited 
to patients who received prior anthracycline.
	DR. VOSE:  I would have to agree with that.  I 
think we can only actually get better results.  So, I don't 
think we should mandate that. 
	DR. DUTCHER:  Okay.  I agree. 
	(c) When compared to Taxol alone, does the 
efficacy profile for Taxol-Herceptin provide sufficient 
additional clinical benefit to outweigh the increased 
incidence of toxicities, particularly infusional toxicity 
and increases in cardiac, hematologic, GI, infectious and 
neurologic toxicities? 
	I think the answer to this is yes.  This profile 
is certainly in favor of the combination.
	DR. VOSE:  I agree. 
	DR. DUTCHER:  Dr. Margolin?
	DR. MARGOLIN:  The times to treatment failure are 
integral of that and progression is still strongly favorable 
for that combination.
	DR. DUTCHER:  So we should vote on (c).  All those 
who would vote yes for (c)?
	[Show of hands]
	Eleven yes and zero no. 
	Question three, when compared to doxorubicin 60 
mg/m2 or epirubicin 75 mg/m2 plus cyclophosphamide 600 mg/m2 
AC chemotherapy, Herceptin used in combination with AC was 
associated with a greater median time to progression by 2.1 
months, and a higher 1-year survival rate, 73 percent versus 
83 percent, but no significant difference in median 
survival.  The patients studied had not received 
chemotherapy for metastatic disease, although they may have 
received hormonal therapy.  Herceptin in combination with AC 
therapy was associated with infusional toxicity.  The 
observed incidence of cardiotoxicity in patients receiving 
AC plus Herceptin was 28 percent as compared to an incidence 
of 7 percent in the AC alone arm.  The incidence of severe 
cardiotoxicity, class III or IV, was 19 percent in patients 
receiving Herceptin plus AC compared with 2 percent in 
patients treated with AC alone.  Other toxicities which 
appeared to be increased in incidence and severity when 
compared to patients receiving AC alone include anemia, 
leukopenia, abdominal pain, diarrhea, dyspnea, and 
infections. 
	(a) Do the data regarding time to progression and 
survival provide evidence of improved efficacy for the 
combination of AC plus Herceptin over AC alone used as 
first-line treatment for metastatic breast cancer?  Dr. 
Miller?
	DR. MILLER:  Similar to the previous discussion, 
you know, it seems pretty clear that it does have benefit 
over AC alone in the efficacy.
	DR. DUTCHER:  Any other comments?  We agree?
	(b) When compared to AC alone, does the efficacy 
profile of AC plus Herceptin provide sufficient additional 
clinical benefit to outweigh the increased incidence and 
severity of cardiotoxicity, 28 percent versus 7 percent, the 
increased incidence of hematologic, gastrointestinal, and 
infectious toxicities and infusion toxicity?  Go ahead.
	DR. WEISS:  Again, as with the agent alone, I 
would say yes, but I think given the 4-fold cardiotoxicity 
incidence with ACH versus AC, again, I think we might insert 
a caveat about a noninvasive cardiac evaluation prior to 
institution of therapy, if everyone agrees. 
	DR. DOROSHOW:  I would like to present a different 
view.  I think that, in fact, Herceptin produces synergistic 
cardiotoxicity with Adriamycin, and I am not at all sure 
that the very modest clinical benefit, though real -- 
certainly the time to progression is real, if not for 
survival, is really worth this synergistic cardiac toxicity, 
in my view. 
	DR. WEISS:  In saying what I said I was hoping to 
avoid causing more damage to already seriously injured 
hearts basically.  I don't disagree with what you say but if 
we do decide to say yes to the question, I think a higher 
cardiac evaluation is important. 
	DR. SEIGEL:  I would like some clarification on 
that because, although there wasn't a vote and not 
necessarily everyone spoke, I got the impression that there 
was a general consensus that even patients getting 
single-agent Herceptin or Herceptin with paclitaxel ought to 
have prior cardiac evaluation.  So, we could give additional 
warning about the higher risk level.
	DR. DUTCHER:  I think the issues are that there is 
something going on with the heart with the molecule by 
itself, and the dosing of the Adriamycin in these regimens 
is right on the cusp of when it starts to interact.  So, 
those are the issues.  Dr. Schilsky?
	DR. SCHILSKY:  Well, I guess I share many of Jim's 
concerns.  In my mind, you know, in this patient population 
there is only a 2-month improvement in median time to 
progression, and you have to weigh that against the risk of 
better than 1 chance or more that the patient will develop 
significant cardiac failure. 
	I am also thinking of this in terms of the fact 
that, sort of in contemporary times, relatively few women 
would actually be getting an anthracycline-based 
chemotherapy regimen for metastatic disease because the vast 
majority would have already had an anthracycline as part of 
their adjuvant therapy.  So, in fact, if Herceptin were not 
approved for use in combination with AC, I think relatively 
few patients would be disadvantaged by that. 
	Then, there is the whole issue of the fact that a 
proportion of patients probably don't benefit from the 
addition of Herceptin at all to their chemotherapy.  That 
has to do with the whole issue of intensity of staining and 
the variability of those data. 
	But, clearly, you know, one might be putting a lot 
of patients at risk for cardiotoxicity with this regimen, 
recognizing that the potential benefit is going to be 
confined to a relatively small subpopulation of the total 
group of patients who are, quote, HER2 positive.  So, I have 
a lot of concerns about this.
	DR. DUTCHER:  Dr. Lipschultz?
	DR. LIPSCHULTZ:  I have some similar concerns 
about the issue of monitoring before therapy.  I think in 
spite the best efforts of everyone involved with these 
studies, it is completely unclear to me what the real 
incidence and extent of cardiac involvement is, and even 
more so than that, really whether anything is effective as a 
predictor of an adverse cardiac outcome, whether it be a 
baseline ejection fraction, serial monitoring, other sorts 
of things, we have no idea from this data whether any 
particular type of screening would be worthwhile. 
	But I share the same concerns with this group as 
to whether the quality of life balance is really clear in 
terms of heart failure, for instance.
	DR. DUTCHER:  Dr. Weiss?
	DR. WEISS:  Yes, I do agree with what you said.  I 
think what I am trying to emphasize is that we would be very 
hesitant to give this agent to someone with an ejection 
fraction  of 15 percent, or something.  I think it is 
important that we know what we are in for before we give 
this potentially very dangerous combination.  That is my 
only point.
	DR. LIPSCHULTZ:  Oh, I agree.  But usually what 
happens in these sorts of situations is it is clear-cut when 
someone has an ejection fraction of 15 percent, but when 
that patient has an ejection fraction of 43 percent and 
seems healthy otherwise, then you are in a dilemma in terms 
of what you do with a magic number like that.  And, it is 
not clear from anything I have heard today that we are at 
all able to deal with that. 
	DR. DUTCHER:  Dr. Margolin?
	DR. MARGOLIN:  I am curious, from Dr. Seigel and 
his colleagues, exactly what the vote to number 3 (b) -- how 
that would influence -- you know, the drug presumably would 
be approved but this would affect the package insert?  Are 
you really going to say this is not approved for use with 
Adriamycin?  What exactly are you going to do with the 
information?
	DR. SEIGEL:  Well, I think the questions obviously 
don't get too highly specific about the labeling because 
what we would like to do is integrate your expert opinion 
into what makes sense.  It is unlikely, unless we heard 
something that would say that, that we would write a 
contraindication to use with Adriamycin.  It may be that, 
rather than have that in the listing of how to administer 
regimens, that that regimen and its outcomes will almost 
surely be described in the clinical pharmacology but may not 
be listed as the others as a so-called recommended dosage or 
administration.  There are a lot of ways to go and, 
depending on what we hear and if you have specific ideas 
about it, we would like to know. 
	DR. MARGOLIN:  It influences how we vote.
	DR. SEIGEL:  Pardon?
	DR. MARGOLIN:  It influences how we vote.
	DR. SEIGEL:  Yes. 
	DR. MILLER:  And we have to sort of figure out 
whether we are lumping or splitting.  Whether or not we are 
going to require that each different drug be looked at 
separately and how it interacts, or whether we are going to 
say that this drug is an effective drug and then let the 
clinical scientists figure out how best to use it as long as 
we document the toxicity and the risk-benefit ratio. 
	Abbie Meyers is not here so I will say what she 
normally says.  You know, the question if we write the label 
too limited, it does, in fact, affect the potential patient 
reimbursement issues.  Also, the risks and benefits for one 
person may be different for the other person. 
	So, I am sort of on the other end.  I think that 
we should request that further studies be done looking at 
that, but that we shouldn't split and say you can use it 
with this but you can't use it with different drugs.
	DR. SEIGEL:  So, if the labeling were to say, for 
example, that Herceptin is indicated for use in second or 
third line in metastatic, and then it is indicated for use 
in combination chemotherapy -- now, typically chemotherapy 
drugs labeling, as I understand it, although I am not an 
oncologist and deal less with them, indicates the approved 
regimens.  But you are suggesting -- it sounds like you are 
suggesting in this case you would simply say it is indicated 
in combination with chemotherapy for first-line treatment of 
adjuvant, in which case we wouldn't be restricting it, and 
that would also open it up to all sorts of other 
chemotherapies that haven't been studied.  Or, we could say 
it would be indicated in combination with paclitaxel, or we 
could say it would be indicated in combination with 
paclitaxel or --
	DR. DUTCHER:  Let's go back to where we were.  
Okay?  We are going far beyond -- let's just talk about 
anthracyclines because some of us are old enough to have 
taken care of patients with Adriamycin cardiotoxicity where 
we couldn't do anything about it. 
	So, I think that the question is, you know, how 
much of a problem is this?  What do we need to decide to do 
about either approving it for that use and/or building in 
monitoring and/or trying to decide what this molecule is 
doing to the heart.  That I think is what we have to do 
right now.  Yes, Dr. Vose?
	DR. VOSE:  No, I think in this type of patient 
population it really comes down to trying to look at the 
risk-benefit ratio and the patients quality of life, and 
does a 2-month improvement in time to treatment failure go 
against a 28 percent cardiotoxicity rate that in some 
patients was not reversible with medication, and their last 
2 months or 3 months are going to be very bad?
	So, I think that we should definitely have this 
information highly available to the physicians so that they 
can read that; so that they know what the risk-benefit ratio 
is.  Personally, I would say that no, it is not a good 
risk-benefit ratio with this particular regimen in that 
population.
	DR. DUTCHER:  Miss Fischler?
	MS. ZOOK-FISCHLER:  Well, that was pretty much 
what I was going to say, but I would personally like to vote 
yes, but I would somewhere like to see a caveat that the 
oncologist prescribing it just keep in mind who the patient 
is.  If the patient is very ill and she will only have a 
2-month benefit, I would not like to see her quality of life 
be diminished any further.  But I wouldn't want to preclude 
voting for it. 
	DR. DUTCHER:  I guess the other question is, is 
there a dose of anthracycline that is less than 350 mg/m2 in 
which we wouldn't see the same effect?
	DR. DOROSHOW:  Well, I think it is unlikely with a 
compound that has a half-life of a week used in combination 
with a therapeutic chemotherapeutic agent that has a 
half-life of several days that it is ever going to be 
possible to find a dosing schedule, unless these agents are 
very disparately administered in which there is a potential 
for interaction, whatever the molecular interaction is.   In 
the same way, I think it is going to be very difficult to 
define a cumulative dose, either cumulative dose or 
schedule, where that is going to be possible. 
	DR. SEIGEL:  Well, it is certainly possible that 
if one were to look at restricting the dose of one or the 
other one might find that one could preserve efficacy and 
decrease toxicity.  That has not been looked at.  For 
example, the Taxol is given, as is discussed in a later 
question, basically until progression of disease.  The 
lowest rate of toxicity for Taxol was noted in the 
single-agent study -- I am sorry, I am talking about 
Herceptin here -- and that may reflect the fact that it is 
least toxic in that, but it also could reflect, in part, 
that those patients had the shortest time to progression.  
They only had a 2- or 3-month time to progression on average 
so they only got Herceptin for a very limited period of 
time. 
	You know, there are a lot of questions still to be 
answered.  I hear what you are saying about not being able 
to answer interaction questions, but it would be less 
obvious to me that you couldn't answer whether there are 
other less toxic but effective regimens. 
	DR. MILLER:  Jay, can you remind us how we dealt 
with this on the biologic committee on the other monoclonal 
antibody that was approved, looking at it as approving it in 
general or whether we looked at it combined with other 
chemotherapy agents?
	DR. VOSE:  It was just by itself, Carole. 
	DR. DUTCHER:  Well, we have had sufficient 
discussion for that.  We can vote on that.  I mean, assuming 
that there will be pretreatment cardiac monitoring, when 
compared to AC alone does the efficacy profile of AC plus 
Herceptin provide sufficient additional clinical benefit to 
outweigh the increased incidence and severity of 
cardiotoxicity and the increased incidence of other 
toxicities? 
	All those that would vote yes?
	[Show of hands]
	Two.  Two, yes. 
	All those that would vote no?
	[Show of hands]
	Eight, no.
	Abstain?  Ms. Beaman, did you vote?  You voted no?  
	Nine, no; two, yes. 
	DR. DUTCHER:  Number four, cardiotoxicity is a 
serious adverse event which was increased in the 
Herceptin-treated patients.  Preclinical studies in monkeys 
given AC plus Herceptin and Taxol plus Herceptin, or 
Herceptin alone did not predict such events.  Clinical 
studies, 648 and 649, as well as all other studies conducted 
with Herceptin have not been designed to adequately measure 
the rate of cardiotoxicity, the risk factors for developing 
cardiotoxicity, or the mechanism of cardiac damage.  There 
is insufficient information upon which to base conclusions 
regarding the identification of patients who are most at 
risk, the specific role that anthracycline therapy may or 
may not have in the development of toxicity, and the rate of 
toxicity in anthracycline-naive patients who do not have 
preexisting cardia disease. 
	(a) Please discuss what limitations, e.g. baseline 
characteristics of patients, dose, schedule of 
administration, monitoring, discontinuation recommendations, 
should be included in a label if Herceptin is approved for 
use with anthracyclines.
	Let's go to (b).  Please discuss elements which 
should be included in future studies designed to evaluate 
cardiotoxicity. 
	Maybe the modification of (a) would be that it 
should be able to show safety with anthracyclines.  But I 
think the real issue here is how are we going to get at more 
information about the mechanism and the safe use of this 
agent in terms of the heart.  Dr. Lipschultz?
	DR. LIPSCHULTZ:  My suggestion would be that in 
future studies that there be a centralized core lab to 
improve the reliability of whatever cardiac parameters you 
obtain, whether it be an ejection fraction -- there tends to 
be tremendous variability in that when one looks at 100-plus 
sites. 
	One should also consider several different types 
of cardiac testing that help give a feel for mechanism of 
injury, and definitions of what defines cardiotoxicity 
should be part of it as well. 
	Then, you know, on the other part of this 
question, it seems from what I have heard today that it is 
still not clear what the mechanism is but if it is 
anthracycline related, it is still unclear to me whether 
patients who were treated with continuous bolus -- a few had 
Zinecard -- but those are some things that may be worth 
considering in subsequent studies. 
	DR. DUTCHER:  Dr. Weiss?
	DR. WEISS:  I basically agree with that.  I would 
personally advocate some standard procedure for quantifying 
LV function.  Whatever is chosen; none are perfect.  But, 
certainly, one of the accepted model systems for 2D ejection 
fraction is probably the most practical if you are going to 
look at a lot of sites. 
	I agree with the notion of a central core lab.  If 
further investigations are going to be done, not clinical 
use but investigations, a central core lab should be reading 
and sorting these things out. 
	DR. LIPSCHULTZ:  I will give you an example.  We 
just completed for the NHLBI a 10-year study of patients at 
risk for cardiotoxicity in a different setting, and it was a 
multicenter study, and shortening fraction of 31 percent, 
which is basically an ejection fraction cut in half, and 
when  you compare the local measurement to a central core 
remeasurement of the exact same studies of 21-51 percent -- 
very wide, and when you are dealing with relatively small 
numbers like this and trying to really understand this, it 
certainly behooves us to have some quality assurance similar 
to what you were talking about with your receptor central 
core labs.  There are also quantitative ways to assess acute 
myocardial injury that the FDA has approved that are 
relatively noninvasive.  We are using those on a variety of 
pediatric POG and CCG studies in a national way, and they 
seem to be easily standardized in another marker for injury.
	DR. DUTCHER:  Dr. Margolin?
	DR. MARGOLIN:  Perhaps the FDA can help the 
sponsor design some very directed studies for defining a set 
of pretreatment cardiac parameters that would allow presumed 
safer treatment, you know, with central lab, and then some 
very specific, precise, uniform monitory, even, say, a Phase 
2 study of Herceptin and Adriamycin or something like that 
in a defined population of patients so that a post-marketing 
report could be generated. 
	DR. SEIGEL:  As I am sure most or all of you are 
aware that when we head toward drug approval we have the 
opportunity to negotiate with the company commitments to 
address key issues.  In that regard, and it doesn't come out 
explicitly in these questions but you mentioned looking more 
at toxicity and how to monitor it in the setting of use with 
anthracyclines.  What about use with other unknown or other 
likely drugs to be used in this setting?  Is that another 
area where there is significant concern that we should be 
getting toxicity data?
	DR. DUTCHER:  Dr. Doroshow?
	DR. DOROSHOW:  Well, I think there are two things 
to be said.  One is that if it is going to be used with 
anthracyclines, irrespective of the preclinical data that 
are available in terms of pharmacokinetics, it would seem 
mandatory to know if there are any toxic interactions that 
could be related to pharmacokinetic antibody interactions 
that could lead to an enhanced cardiac toxicity with 
Adriamycin.  So, that is a simple thing to do.  It really 
ought to be done. 
	I think it is also true that since we don't know 
the mechanism of the interaction either at the tumor cell 
level or in the heart, these kinds of things really will be 
required with agents that could potentially have cardiac 
toxicity.  Taxol is not a major cardiotoxin but together 
with Herceptin we have results that are very significant, 
and I think that you can't exclude potential -- that has to 
be studied in humans because the preclinical models are not 
available. 
	DR. WEISS:  And, I think it is important to point 
out one way or another post-marketing what we all now know, 
that this is potentially a quite cardiotoxic agent, and that 
it is very important to know what kind of ventricular 
function you are dealing with before you give this to a 
patient with or without the various agents under discussion.
	DR. DUTCHER:  In terms of other agents, I mean it 
has acted very differently with Taxol or AC.  So, I don't 
know that you would know how it is going to behave in 
combination with other chemotherapeutic agents.  So, you 
know, I don't think that there should be an onerous burden 
of a Phase 1 with every chemotherapeutic agent by any 
stretch, but I do think that there needs to be additional 
information gathering as the drug is used more widely and in 
combination with other agents.  That just is prudent. 
	DR. WEISS:  A possible suggestion of follow-up is 
noninvasive studies over time, I don't exactly know how many 
or how often, but some sort of follow-up monitoring would be 
important to consider. 
	DR. SEIGEL:  Let me solicit a little more advice 
regarding the first part of this question, which deals less 
with what studies might be done and more perhaps with what 
might go into labeling.  I gather, as I have noted before, 
that you have indicated that there is a consensus that 
patients ought to be pre-screened for heart failure and 
probably with ejection fraction determinations, although we 
have certainly heard loud and clear what we also see, which 
is you can't determine from the database that those patients 
are at higher risk.  I guess the concern is that they may 
have less reserve and, so, we haven't specifically heard but 
I would like to hear, if anyone felt this, that patients 
with any particular amount of heart failure at baseline 
ought to be contraindicated or not treated.  I would be 
interested in your thinking about that. 
	Another thing, I guess, that I would like to think 
through is what then ought to be recommended follow-up.  You 
do all of this; you get the information.  Then, do you 
simply follow the patient clinically for symptoms, or should 
there also be recommendation for any further routine 
evaluation even in the asymptomatic patient for cardiac 
toxicity?
	DR. WEISS:  There might be a recommendation with 
regard to heart failure, but if a person is having some 
degree of heart failure, which the group could agree on, 
class III or class IV failure, or whatever, that the drug 
either be used with extreme caution or not at all. 
	I do agree with the need for some sort of 
noninvasive follow-up monitoring over time.  As I said, I 
don't know how often that might be done, but I don't think 
that the monitoring should stop once the drug has been 
given. 
	DR. LIPSCHULTZ:  I believe it is clinical practice 
by most physicians that if a patient has clinical congestive 
heart failure that they not continue to receive 
anthracycline.  I would continue to hold that true for this 
situation as well. 
	DR. SEIGEL:  Would you also say that patients with 
clinical heart failure should not be begun on this regimen?
	DR. LIPSCHULTZ:  That is the usual practice with 
anthracycline therapy as well. 
	DR. DUTCHER:  Jay, I guess the only problem is we 
don't really know what this drug is doing to the heart.  So, 
I think that that would be probably your gut feeling, but 
you might have somebody who has had four different drugs, 
you know, and they understand that it is a risk and they 
want to have this treatment, and I don't think that that 
should preclude it.  I just think we have to get more 
information.  I mean, maybe it is HLA related; or maybe it 
is Crest toothpaste related.  We just need to find out what 
it predicts for, and is it everybody; is it a certain group.  
So.  Okay, can we go on? 
	Question five revolves around schedule and 
duration of treatment.  In all studies, Herceptin was 
administered weekly until disease progression.  A shorter 
duration of therapy may be equally efficacious.  If 
Herceptin is approved, what post-marketing commitments 
should be made to verify that administration to time of 
progression disease is optimal?
	DR. SCHILSKY:  It has to be studied in an 
appropriately designed clinical trial.  I mean, it may be 
that a shorter duration of administration will not be 
equally efficacious.  The only way to find out is to do the 
appropriate trial.
	DR. VOSE:  But I don't know that we need to 
mandate that for them as part of a mandated post-marketing 
study.  I think that the field will do those studies 
appropriately.
	DR. SIMON:  We don't know that information for 
most chemotherapeutic drugs, and to really get that 
information would be very difficult because it would require 
essentially doing a therapeutic equivalence trial in a 
setting where the size of the benefit is actually very 
small.  So, you would have to size it -- first of all, you 
would have to only include responders probably in the 
randomization, and then you would have to size it so you 
could detect whether you were losing, say, half the benefit.  
It would be a very, very large trial. 
	DR. DUTCHER:  Okay.  I think we did address some 
of number six, which is about pharmacokinetics.  
Pharmacokinetic data from the clinical and preclinical 
studies suggest that following administration in combination 
with paclitaxel, Herceptin serum concentrations are higher 
compared to those following administration of Herceptin as a 
single agent.  This same effect is not apparent for the 
combination of Herceptin with AC therapy.  In addition, 
unexpected toxicities have been observed which were not 
predicted by preclinical testing.  There is only anecdotal 
data to date on the combination of Herceptin with other 
anti-tumor agents.  Given this information, if Herceptin is 
approved, should its indication as a combination therapy be 
limited to use only in those combinations whose 
pharmacokinetic interactions have been studied in a 
specific, prospective fashion?
	DR. SEIGEL:  We have received a lot of comments on 
it.  If there are more, they are welcome but I don't think 
we need any more discussion. 
	DR. DUTCHER:  Okay, question number seven is the 
immunohistochemistry question.  Going to the last two 
sentences, in patients with 2+ overexpression -- let's see, 
no, I am going to go up a sentence. 
	While neither study 648 nor 649 was designed to 
determine the difference in clinical benefit between 
patients whose tumors were 2+ and those whose tumors were 3+ 
by immunohistochemistry testing for HER2/neu protein 
overexpression, exploratory analyses suggest that the 
benefits conferred by the addition of Herceptin to AC or T 
are largely or entirely seen in patients whose tumors 
exhibited 3+ overexpression of HER2/neu in study 648.  In 
patients with 2+ overexpression, there was no suggestion of 
benefit in time to progression, overall response rate, or 
survival.  The response rate to single agent Herceptin in 
study 649 was also significantly lower for patients with 2+ 
overexpressing tumors as compared to those with 3+ 
overexpressing tumors. 
	(a) Given the known risk-benefit profile, should 
the indication for single agent Herceptin as second- or 
third-line therapy for metastatic breast cancer be limited 
to those patients who are 3+ by immunohistochemistry 
testing?  Dr. Margolin?
	DR. MARGOLIN:  I think that given the fact that 
the data we looked at were exploratory and not based on 
pre-stratification, and the fact that there is still a 
pretty big overlap in those assays between 2+ and 3+, we are 
not ready to limit this indication to patients who are 3+. 
	DR. DUTCHER:  Dr. O'Leary?
	DR. O'LEARY:  I would like to emphatically 
disagree, and I would like to disagree because of looking at 
the confusion matrix between the DAKO antibody and the test 
data set, considering the fact that about 80 percent of 
these tumors are expected to be not overexpressing. 
	If you were to include the 2+ in the DAKO assay 
you would have about as many people showing up who would be 
positive in the DAKO assay, 2+ and above, who were not in 
the group shown to have clinical benefit as you would in the 
group shown to have clinical benefit.  If you restrict it to 
3+, it looks like you probably would be expected to exclude 
perhaps 20 percent of folks that might possibly benefit. 
	It seems to me that that lab interaction right now 
and the fact that this has been validated against, you know, 
sort of the wrong assay, and the principle of "do no harm" 
in this case would suggest that if you use the DAKO assay 
you are going to be including a lot of patients in therapy 
for whom benefit has not been demonstrated. 
	DR. DUTCHER:  Dr. Miller?
	DR. MILLER:  I agree with Dr. O'Leary.  I think 
that this drug should be used where we think it has the most 
chance of being efficacious.  So, I would use the patients 
who are 3+.
	DR. DUTCHER:  Dr. Vose?
	DR. VOSE:  I have to disagree with that.  I think 
that there is enough question about the assays and I 
wouldn't want to exclude 20 percent of patients that could 
possibly get a benefit from this when we have put out all 
these other stipulations as far as not using it with AC and 
doing the cardiac monitoring, and doing everything else.  I 
think that would be a problem, to exclude that 20 percent of 
patients given that the we have to really evaluate that.
	DR. SEIGEL:  I am sorry, 20 percent is which?
	DR. VOSE:  Well, using the numbers that you were 
saying, that 20 percent of patients, if we just go with 
using the 3+, we would exclude 20 percent of patients that 
could potentially get benefit from the Herceptin.
	DR. MILLER:  Yes, but that is 20 percent of 
patients who would be read as 3+ --
	DR. VOSE:  Right. 	
	DR. MILLER:  -- and 17-30 percent of those 
patients would respond.  So, you are actually benefiting 30 
percent of 20 percent.  It is a much smaller number --
	DR. VOSE:  I understand it is a smaller number 
overall, but I think given the stipulations that we have 
said and the fact that the test is not perfect and needs to 
be further validated, I don't think it is proper to exclude 
those patients. 
	DR. SEIGEL:  If we go with 1+ we are excluding 5 
or so percent of the people that were 3+ by the study assay 
probably, and if we go with 2+ we would be excluding maybe 
6, I guess.  I guess we are really in the range of 3-5 
percent of the patients.  Is that okay, or should we just 
not use a test? 
	By the way, we are not going to ask for a vote 
here, and I should explain that these data will be presented 
in considerably greater length and detail, with a lot more 
time for discussion, to the device panel on Friday.  We are 
going to integrate all of that information.  Having had you 
suffer with us, if you will, or having had the benefit with 
us of this extensive data, we really want to appreciate and 
integrate your advice.
	DR. VOSE:  It just seems to me that it hasn't been 
validated or not validated enough that we can answer this 
question.  I think it needs further study. 
	DR. MILLER:  I think the device panel, on Friday, 
is going to ask different questions than what you are asking 
as a clinical panel here.  I mean, I think the vote on that 
would be much here than on Friday.  I am going to be there 
on Friday but I think this is the panel you want to ask.
	DR. DUTCHER:  Dr. Simon?
	DR. SIMON:  I think there are two aspects to it.  
One is the aspect that Dr. Margolin was alluding to.  In 
general, it is dangerous to sort of say, well, post hoc I am 
going to require demonstrating an effect in every subset.  
In this case, however, it is not every subset; it is a 
subset which, although it may not have been defined 
prospectively, is a subset which is inherently relevant.  
So, even though it is not a clear-cut situation, I feel, 
given that it looked like there was not one iota of evidence 
that there was a benefit of including the antibody with 
chemotherapy in the patients who were 2+, that in itself 
would start getting into issues of assay reproducibility.  
So, I would say you probably shouldn't restrict it to 3+.
	But then when you get to issues of assay 
reproducibility, I think it even becomes more compelling to 
restrict it to patients with 3+ because if you look at the 
matrix that was put up there, if you look at the row that 
corresponded to 2+, 12 percent of the patients in that row 
were 3+.  All the rest of them were either 2+, 1+ or 0+, and 
there were many, many more of them who were 1 and 0+ than 
there were who were 3+. 
	So, whereas you may say, well, yeah, if I included 
the 2+ -- it really works with the 3+ patient and, 
therefore, I want to do 2+ because I don't want to lose 
those 12 percent, by doing that you are just including a 
whole ton of women in whom there doesn't seem biologically 
or empirically to be any benefit. 
	DR. VOSE:  Do you think there are enough numbers?
	DR. SIMON:  There were 150-something women in the 
second row.
	DR. VOSE:  Right.  Do you think that is enough to 
validate that assay?
	DR. SIMON:  Well, I think immunohistochemical 
assays are notoriously unreproducible. 
	DR. VOSE:  Right.  That is the problem. 
	DR. SIMON:  I mean, I believe that.  I believe you 
have that spread. 
	DR. DUTCHER:  Why don't we let Dr. Shak make one 
rebuttal comment?  Be very brief. 
	DR. SHAK:  Being very brief at this late hour, we 
did point out the interaction but I want to reemphasize just 
two points.  Number one, it is an interaction and not a test 
that excludes benefit, and that is very important.  In the 
study that was overall negative it would be inappropriate to 
identify a subgroup that was positive and try to make a 
claim for proof of efficacy. 
	The second point is that in the exploration, in 
fact, there are examples of benefit in 2+ patients.  It was 
pointed out in the single-agent study that there was a 6 
percent response rate.  Well, those are real and meaningful 
for those patients.  Again, the confidence intervals around 
that are large, and those could be a significant number of 
women who have few other options in a very advanced setting.
	[Slide]
	Probably even more important is now a subgroup of 
a stratum, namely the paclitaxel group.  In the paclitaxel 
group in 648 in the 2+ subgroup the response rate was 21 
percent with Herceptin plus paclitaxel, and 11 percent with 
paclitaxel alone. 
	DR. SIMON:  That doesn't seem to agree with the 
data that the FDA presented.
	DR. SHAK:  Well, the FDA presented data overall, 
which showed that overall there was no difference in 
response rates.
	[Slide]
	With regard to time to progression, again, there 
is clearly evidence of a lesser magnitude of benefit but, 
again, we would be cautious in concluding from this that it 
would indicate that there was no benefit. 
	We would recommend, and I think it is what we have 
recommended, that it be that the insert clearly state and 
inform patients and physicians that it may be the case that 
there are lesser magnitudes of benefit with lower levels of 
HER2 overexpression.  That would then allow within the 
context of the overall information provided with benefits 
and risks for individual treatment decisions to be made.
	DR. DUTCHER:  Thank you.  Dr. Simon?
	DR. SIMON:  As a practical matter, given what was 
shown on that slide in terms of the reproducibility of that 
assay for 2+, the only way you are going to try to reclaim 
the small potential gain is by including the vast majority 
of patients -- I mean, more of them are going to be 1+ and 
0+ than are even going to be 2+. 
	DR. DUTCHER:  Dr. Schilsky?
	DR. SCHILSKY:  This is a tough issue, and I 
brought his up earlier.  I think under most circumstances I 
would actually completely agree with Rich Simon's analysis, 
but that depends on having a lot of confidence in the data 
that we have at the moment and on that concordance chart 
that was shown, which was based on specimens not even 
derived from the trial. 
	I actually come down on the side of thinking it 
would be a mistake at this point to restrict the use of this 
to just the 3+ patients because I don't actually know what 
3+ means.  There are going to be other assay methodologies 
that are available in the future, and I think that it is 
going to take some time in the context of the prospective 
use of Herceptin, with clearly defined assay methodologies, 
to sort this all out, and it probably would not be wise to 
limit it at this point. 
	DR. DUTCHER:  Mixed reviews.
	DR. SEIGEL:  Let me ask another question which 
isn't exactly here but is related to that.  Is there a 
relatively strong sense, if I read between the lines, that 
if there were to be approval of this drug and of the DAKO 
test kit, that there ought to be studies looking at it?  We 
heard in the comment period that there are studies of 0 and 
1+ patients under way now.  I don't know with what test kit 
or what studies, but it seems like whatever is out there 
clinically available for screening for overexpression, it 
would be nice to have information as to extent to which 
results from that correlate, if not with survival which 
would require a randomized control, at least with response 
rate outcome. 
	DR. DUTCHER:  I think what you would like to see 
is some kind of a kit so that you really could show 
reproducibility in terms of multiple different people using 
it because right now, you know, some people call another 
pathologist and say, "is this positive or negative?  Look 
what I see."  So, I am concerned that, you know, there is 
going to be a lot of variability for a long time, but that 
doesn't mean that we are not going to treat patients based 
on that data.  Dr. O'Leary?
	DR. O'LEARY:  My comment is that even if you 
address the reproducibility issues perfectly, it is the fact 
that the test kit that is being looked at is not the test 
kit that was being used to determine clinical benefit.  It 
becomes a real issue here, and it would be awfully nice to 
see a rather direct relationship established at some point, 
assuming these are approved eventually, between the test kit 
performance and the clinical responses of the patients 
because this is a very, to me, unsatisfying surrogate. 
	DR. SEIGEL:  Yes, in that regard, I would like to 
put out a little bit of a public plea.  In many cases, and I 
can't speak specifically to this one, where studies are 
done, and we have a lot of them, where therapy is dependent 
on expression of a specific antigen, we ask, where possible 
and storable -- or on circulating levels of cytokines or 
whatever they are based on, that specimens from the patients 
in the study be saved and stored so that subsequent tests 
for whatever that is can be used to study those patients to 
see what determinations are made on the basis of the results 
of that test.  So, just a little plea for anybody listening 
or watching, and I certainly hope that that will more often 
than not be the case. 
	One thing perhaps I should toss out just as a 
flyer and, again, we are not on the verge of making 
decisions without a lot more discussion, but in integrating 
a lot of disparate comments, it occurs to me that one 
possible approach would be to write an indication that says 
that this should be used in patients who are strongly 
positive overexpresssors, and then to put into the labeling 
both the data showing that 2+ with the study assay had -- I 
wouldn't say not an iota but certainly not a lot of evidence 
in terms of efficacy, and the data showing the lack of 
correlation, with some commentary but leaving perhaps the 
indication not specifically linked to a specific outcome or 
a specific test, but with some commentary, as I said, 
pointing out, as I think Dr. Simon has, the fact that 
patients 2+ with DAKO are all over the board, for example.  
Would that be a consistent way to address a number of the 
concerns that we have heard?
	DR. VOSE:  I think that would be very acceptable.  
If you say strongly positive, that would rule out those 
patients --
	DR. SEIGEL:  And then provide the data --
	DR. VOSE:  Provide the data and then they could 
make the decision.
	DR. SEIGEL:  Yes.  Again, I am not saying we have 
decided to do that, but that would be one of the options 
that we might consider.
	DR. DUTCHER:  Dr. Norton?
	DR. NORTON:  Just as a clinician who has used the 
drug a lot, it is almost a plea -- we had any number of 
patients that tested 2+ with polyclonal antibodies that we 
used, and then tested 3+ with the Genentech antibody and had 
very good responses to therapy.  I can just see, you know, 
the panic of having a situation where somebody was excluded 
from being able to treat these patients because of a very 
subjective test -- 2+, 3+ -- 3+ usually is obvious; 0 is 
usually obvious; 2+ can be all over the place and it is a 
very subjective test, and I think, you know, putting this 
sort of artificial numerical descriptor on it could be very 
dangerous and very destructive. 
	DR. DUTCHER:  I don't see any more pages for the 
questions so I think we are dismissed. 
	DR. SEIGEL:  Thank you very much.
	DR. DUTCHER:  We will be back here in twelve 
hours. 
	[Whereupon, at 7:45 p.m., the proceedings were 
recessed until 8:00 a.m., Thursday, September 3, 1998]
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