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' SCIENTinC MISCONDUCT IN BREAST CANCER RESEARCH ^~ 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 r --*.I-— --:,- '^^ 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 (chairman) 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 treatment 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 response 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 handling 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 community and the Federal Government fall down on thejob. It is, I think, without necessity that the Chair points out that involved 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 fabricated 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 audits 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 fraudulent 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 investigation. 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 principal investigator. Last week ORI initiated a misconduct investigation 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 funding 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 subcommittee 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 problems. 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 attributable 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 subcommittee 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 reporting tamoxifen deaths, show that responsible audits and oversight 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 government'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 cancer, representatives of concerned women's health groups, and officials 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 perhaps 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