Table Of Content' SCIENTinC MISCONDUCT IN BREAST CANCER
RESEARCH
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Y 4, EN 2/3: 103-143
Scientific llisconduct in Breast Can...
HEARINGS
BEFORE THE
SUBCOMMITTEE ON
OVERSIGHT AND INVESTIGATIONS
OF THE
COMMITTEE ON
ENERGY AND COMMERCE
HOUSE OF REPRESENTATIVES
ONE HUNDRED THIRD CONGRESS
SECOND SESSION
APRIL 13 and JUNE 15, 1994
Serial No. 103-143
Printed for the use of the Committee on Energy and Commerce
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8 re.
U.S. GOVERNMENT PRINTING OFFICE
84-5lOCC WASHINGTON : 1994
ForsalebytheU.S.GovernmentPrintingOffice
SuperintendentofDocuments,CongressionalSalesOffice,Washington,DC 20402
ISBN 0-16-046276-2
' SCIENTinC MISCONDUCT IN BREAST CANCER
RESEARCH
^~
Y 4. EN 2/3: 103-143
Scientific Hisconduct in Breast Can...
HEARINGS
BEFORE THE
SUBCOMMITTEE ON
OVERSIGHT AND INVESTIGATIONS
OF THE
COMMITTEE ON
ENERGY AND COMMERCE
HOUSE OF REPRESENTATIVES
ONE HUNDRED THIRD CONGRESS
SECOND SESSION
APRIL 13 and JUNE 15, 1994
Serial No. 103-143
Printed for the use of the Committee on Energy and Commerce
/
- - 4dy
4^.
U.S. GOVERNMENT PRINTING OFFICE
84-5lOCC WASHINGTON : 1994
ForsalebytheU.S.GovernmentPrintingOffice
SuperintendentofDocuments,CongressionalSalesOffice,Washington,DC 20402
ISBN 0-16-046276-2
COMMITTEE ON ENERGY AND COMMERCE
JOHN D. DINGELL, Michigan, Chairman
HENRY A. WAXMAN, CaUfornia CARLOS J. MOORHEAD, CaUfornia
PHILIP R. SHARP, Indiana THOMAS J. BLILEY, Jr., Virginia
EDWARD J. MARKEY, Massachusetts JACK FIELDS, Texas
AL SWIFT, Washington MICHAEL G. OXLEY, Ohio
CARDISS COLLINS, IlUnois MICHAEL BILIRAKIS, Florida
MIKE SYNAR, Oklahoma DAN SCHAEFER, Colorado
W.J. "BILLY" TAUZIN, Louisiana JOE BARTON, Texas
RON WYDEN, Oregon ALEX MCMILLAN, North Carolina
RALPH M. HALL, Texas J. DENNIS HASTERT, IlUnois
BILL RICHARDSON, New Mexico FRED UPTON, Michigan
JIM SLATTERY, Kansas CLIFF STEARNS, Florida
JOHN BRYANT, Texas BILL PAXON, New York
RICK BOUCHER, Virginia PAUL E. GILLMOR, Ohio
JIM COOPER, Tennessee SCOTT KLUG, Wisconsin
J. ROY ROWLAND, Georgia GARY A. FRANKS, Connecticut
THOMAS J. MANTON, New York JAMES C. GREENWOOD, Pennsylvania
EDOLPHUS TOWNS, New York MICHAEL D. CRAPO, Idaho
GERRY E. STUDDS, Massachusetts
RICHARD H. LEHMAN, California
FRANK PALLONE, Jr., New Jersey
CRAIG A. WASHINGTON, Texas
LYNN SCHENK, California
SHERROD BROWN, Ohio
MIKE KREIDLER, Washington
MARJORIE MARGOLIES-MEZVINSKY,
Pennsylvania
BLANCHE M. LAMBERT, Arkansas
Alan J. Roth, StaffDirector and ChiefCounsel
Dennis B. Fitzgibbons, Deputy StaffDirector
Margaret A. Durbin, Minority ChiefCounsel and StaffDirector
Subcommittee on Oversight and Investigations
JOHN D DINGELL, Michigan, Chairman
SHERROD BROWN, Ohio DAr«I SCHAEFER, Colorado
MARJORIE MARGOLIES-MEZVINSKY, CARLOS J. MOORHEAD, CaUfornia
Pennsylvania JOE BARTON, Texas
HENRY A. WAXMAN, CaUfornia FRED UPTON, Michigan
CARDISS COLLINS, Illinois
RON WYDEN, Oregon
JOHN BRYANT, Texas
Reid P.F. Stuntz, StaffDirectorIChiefCounsel
Peter D.H. Stockton, Research Analyst
Bruce F. Chafin, Special Assistant
John J. Hambel, Minority Counsel
(II)
CONTENTS
Page
Hearings held on:
April 13, 1994 1
June 15, 1994 101
Testimony of:
Bivens, Lyle W., Director, Office of Research Integrity, Department of
Health and Human Services 51
Broder, Samuel, Director, National CancerInstitute 45, 198
Chabner, Bruce, Director, Division ofCancerTreatment, National Cancer
Institute 45
Detre, Thomas, senior vice chancellor of health sciences. University of
Pittsburgh 134
Fisher, Bernard, former chairman. National Surgical Adjuvant Breast
and Bowel Project, University ofPittsburgh 168
Friedman, Michael A., Associate Director, Cancer Therapy Evaluation
Program, National Cancer Institute 45
Herberman, Ronald B., interim chairman. National Surgical Adjuvant
Breast and Bowel Project, University ofPittsburgh 138
Milbauer, Alan, vice president, external affairs, Zeneca Pharmaceuticals
Group 107
O'Connor, J. Dennis, chancellor, UniversityofPittsburgh 132
Onex, Joseph, counsel to Bernard Fisher, University ofPittsburgh 168
Patterson, John, international medical director, Zeneca Pharmaceuticals
Group 107
Pearson, Cjrnthia A., program director, National Women's Health Net-
work 20
Plourde, Paul, senior director, Clinical and Medical Affairs, Zeneca Phar-
maceuticals Group 107
Schroeder, Hon. Patricia, a Representative in Congress from the State
ofColorado 8
Sigal, Jill Lea, consultant, Washington, DC 28
Snowe, Hon. Olympia, a Representative in Congress from the State of
Maine 10
Varmus, Harold, Director, National Institutes ofHealth 43
Visco, Fran, president, National Breast Cancer Coalition 12
(III)
SCIENTIFIC MISCONDUCT IN BREAST
CANCER RESEARCH
WEDNESDAY, APRIL 13, 1994
House of Representatives
Committee on Energy and Commerce,
Subcommittee on Oversight and Investigations
Washington, DC.
The subcommittee met, pursuant to notice, at 10:05 a.m., in room
2123, Rayburn House Office Building, Hon. John D. Dingell (chair-
man)
presiding.
Mr. Dingell. The subcommittee will come to order.
Today the subcommittee will examine a number of important is-
sues associated with serious falsification and fabrication of data in
some of the Nation's most important clinical trials on the treat-
ment and prevention of breast cancer, the National Surgical Adju-
vant Breast and Bowel Project, NSABP, led by Dr. Bernard Fisher
ofthe University of Pittsburgh.
A
particular focus ofthis hearing is the Federal Government's re-
sponse to these problems. This case has major implications for
thousands of patients who have participated in NSABP studies for
decades, for the American taxpayers who have funded NSABP
studies in amounts in excess of $100 million, and for maintaining
the public trust in the integrity ofscience.
Regrettably, this is only the latest in a series of cases that the
subcommittee has felt it necessary to examine. The subcommittee's
involvement in examining, investigating and monitoring the han-
dling of cases of scientific misconduct dates back to 1988 when the
subcommittee held its first hearing on the issue.
Many in the scientific community have resisted outside scrutiny
and others have sought to minimize the problem. But as we see
today, scientific misconduct is a very real problem that requires an
intensive and aggressive response by the scientific community itself
and by the Federal Government. The case before us is a vivid re-
minder of how poor the response of the scientific community can
be and how serious consequences may be when the scientific com-
munity and the Federal Government fall down on thejob.
It is, I think, without necessity that the Chair points out that in-
volved in this matter is not only the confidence of the country in
science, the questions ofexpenditure ofpublic money, but the peace
ofmind of literally millions ofwomen in the United States who feel
great concern about the possibility of cancer and the consequences
to them ofbad science.
Before we get into the specifics of this case, the Chair would like
to point out that we will hear today important reassurances for
(1)
American women, and we believe that is good. According to the Na-
tional Institutes of Health, the National Statistical Analyses by the
National Cancer Institute, NCI, contractor indicate that the major
findings ofthe NSABP lumpectomy/mastectomy study remain valid
even without the inclusion of the fraudulent data. However, be-
cause recent revelations have shaken confidence in the entire
study, the Chair notes that audits are both necessary and under
way to confirm the validity of the remainder of the data in the
NSABP database.
What this case shows, however, and what should continue to be
of concern to all Americans are major problems in the handling of
this matter by all concerned. Patient records were falsified and fab-
ricated for over 13 years before NSABP's initial discovery in June
of 1990 of data discrepancies at Montreal's St. Luc Hospital. There
was no follow-up until September 1990, when Pittsburgh sent two
staffers to Montreal, who not only confirmed this discrepancy but
identified a number of others. In December one of the NSABP
audit staffers wrote a memorandum describing that on two occa-
sions St. Luc had continued to report follow-up on patients who
had been dead for 6 to 8 months.
I have had signatures on petitions which were filed against me
by candidates of people who were dead, but I assumed that went
on in politics and not in science.
At the beginning of December 1990 Dr. Fisher told Dr. Poisson,
who led the questioned work, that he had a data problem and that
NSABP was sending a team to Montreal to investigate. Despite
talking with the target of the investigation, Pittsburgh and Dr.
Fisher still had not disclosed the problem to NCI.
In February 1991 Pittsburgh sent its audit report to Dr. Poisson
at St. Luc at which time he confessed to falsifying and fabricating
records. About a week later Pittsburgh formally notified NCI of the
fraud. Eight months had elapsed since NSABP's discovery of the
fabricated and falsified data. The Office of Research Integrity, ORI,
of the Department of Health and Human Services was notified and
then began its investigation.
In May 1991 Dr. Poisson admitted his fraud and was debarred
for life by the U.S. Food and Drug Administration from performing
research involving investigational drugs.
On July 3, 1991, Dr. Samuel Broder, director of NCI, was briefed
on the status of OKI's St. Luc investigation in which ORI had
found "94 cases involved data falsification or fabrications which can
be documented."
solidly
Dr. Broder concluded that the fraudulent St. Luc data should be
removed, that all previously reported studies should be reanalyzed
and the reports published on the reanalysis of the work.
Reanalyses have dribbled out over time from Pittsburgh to NCI.
However, to this date, some 3 years later, no reanalysis has been
published. In fact, the New England Journal ofMedicine has stated
that it will not accept NSABP's reanalysis manuscript until the au-
dits are completed.
In addition. Dr. Broder concluded that no St. Luc's data should
be included in any future publications. However, this was sum-
marily ignored by Dr. Fisher. Dr. Fisher submitted at least 13 pa-
pers that contained fraudulent St. Luc data, of which seven have
now been published.
Despite Dr. Broder's call for an immediate reanalysis, Pittsburgh
did not present a reanalysis until March 1992. This reanalysis was
a simple slide show for the NCI/ORI staff, claiming that the origi-
nally published conclusions remained unchanged when the fraudu-
lent data were removed. NCI/ORI accepted this account, and based
on the assumption that the public health was not at risk for the
next year, NCI/ORI insisted on a blackout of news about the inves-
tigation.
Between 1992 and 1994 NCI sporadically, and only half-
heartedly, encouraged NSABP to complete a manuscript reporting
the reanalysis, to significantly upgrade its audit procedure, and to
establish a data monitoring committee. Pittsburgh moved forward
at an equally halfhearted pace.
After public disclosure of this debacle, Pittsburgh delivered its
reanalysis to NCI in a matter of days. NCI's internal statistician
had significant concerns about the adequacy.
Recently NCI discovered NSABP was nearly 1 year behind in
scheduling site visit audits and 3 years behind in submitting site
visit reports to NCI. Among the audit reports that were submitted
there were numerous instances in which significant discrepancies
apparently were left without any investigation or other follow-up.
For example, during an emergency site visit to Pittsburgh NCI
uncovered a Pittsburgh audit report dated September 1993 which
included evidence of serious irregularity at St. Mary's, another
Montreal hospital. Despite the repercussions of the St. Luc's fraud,
Pittsburgh did not report this new problem to NCI, apparently
thereby contributing to the recent removal of Dr. Fisher as prin-
cipal investigator. Last week ORI initiated a misconduct investiga-
tion ofthis apparently falsified data.
One of the reasons we are here today is that no one followed the
direction of the director of the NCI. Top NCI officials ignored the
director's instructions. Pittsburgh ignored the directions ofits fund-
ing institution. In fact, top NCI officials have complained to the
subcommittee staff that they could not even get Dr. Fisher to re-
turn their phone calls, let alone to take direction from NCI.
This illustrates a central problem identified in numerous sub-
committee investigations of scientific misconduct: Who is in charge,
the NIH, which is the funding institution, or other funding institu-
tions, or the prominent investigators? NIH's capability and willing-
ness to manage and oversee federally funded research continues to
be a key question, and millions of dollars are being spent on this
kind of research.
A separate but related matter to be discussed today underlines
the importance of disclosing and aggressively responding to prob-
lems. Dr. Fisher and Pittsburgh did not adequately investigate
deaths involved in the use of tamoxifen in clinical trials under his
supervision, nor did they notify NCI and ICI in a timely manner.
Tamoxifen has been widely used in treatment studies for years,
but only in the last 2 years has tamoxifen been given to healthy
women in a prevention trial. At the time of the initiation of this
study there were concerns about side effects, particularly uterine
and other cancers, but not a single death at this time had been at-
tributable to this risk.
However, on June 25, 1991, the first tamoxifen-related uterine
cancer death occurred. The death was reported to Pittsburgh on
August 5, 1991, but Dr. Fisher claims it took him 2 years to deter-
mine the cause ofdeath. He told the staffofthis subcommittee that
he was unable to obtain the autopsy analysis from the hospital in
his study.
In fact, by October 1993 Dr. Fisher was aware of at least four
uterine cancer deaths attributable to tamoxifen. Just last Friday
the FDA and the manufacturer warned doctors about the increased
risk associated with tamoxifen. The company has told the sub-
committee staffthat it first learned ofuterine cancer deaths caused
by tamoxifen when it was informed by NCI, not Dr. Fisher, in De-
cember 1993.
Both ofthese matters, the St. Luc false data and the delay in re-
porting tamoxifen deaths, show that responsible audits and over-
sight are critical to the maintenance of trust and to scientific
progress. The challenge before us is to make the scientific process
more open and more accountable without politicizing it or burden-
ing it.
In recent years the Congress has attempted to augment the gov-
ernment's ability to combat scientific misconduct. For example, in
1992 we passed the Generic Drug Enforcement Act, which debars
from FDA application-related work those involved in falsifying
drug testing data provided to the FDA. In 1993 we passed the NIH
Revitalization Act, which requires the development of research in-
and
tegrity, policy regulations.
These statutes help, but they do not substitute for administrative
vigilance by NIH nor do they substitute for awareness and action
by the scientific community, which has the first and, indeed, the
principal responsibility of policing itself, a matter on which it must
succeed or other measures will have to be taken by statute or by
other action by the government.
The witnesses today include a woman victimized by breast can-
cer, representatives of concerned women's health groups, and offi-
cials from HHS. These include the director of NIH, the director of
NCI, the director of the Office of Research Integrity. The Chair an-
nounces with regret that Dr. Fisher was unable to testify, citing
health reasons. ICI/Zeneca, the manufacturer of tamoxifen, claimed
inability to provide witnesses from the United Kingdom on a week's
notice. The committee may be interested in hearing them on per-
haps greater notice or perhaps a more interesting hearing at a
later time.
We thank the witnesses for appearing before us today and we
look forward to their testimony.
The Chair recognizes the distinguished gentleman from Colorado
for an opening statement.
Mr. SCHAEFER. I thank the Chair. I really appreciate the Chair
holding this hearing this morning.
Americans are perhaps the best informed people inhabiting the
earth. CNN brings them news 24 hours a day, and the tele-
communications industry's super highways transfer certain vital
information at the blink of an eye. But when it comes to making
