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S. HrG. 106-447 GENE THERAPY: IS THERE OVERSIGHT FOR PATIENT SAFETY? HEARING BEFORE THE SUBCOMMITTEE ON PUBLIC HEALTH OF THE . COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS UNITED STATES SENATE ONE HUNDRED SIXTH CONGRESS SECOND SESSION ON EXAMINING CERTAIN ISSUES REGARDING PATIENT SAFETY IN GENE THERAPY CLINICAL TRIALS, FOCUSING ON FETDANETR ALT OOVUEDR SIGHT PRO- CEDURES AND GUIDELINES FOR INFORMING PATIENTS AND THEIR FAMILIES OF POTENTIAL RISKS AND BENEFITS OF GENE THERAPY FEBRUARY 2, 2000 Printed for the use of the Committee on Health, Education, Labor, and Pensions oe U.S. GOVERNMENT, PRINTING OFFICE 62-393 CC WASHINGTON : 2000 For sale by the U.S. Government Printing Office Superintendent of Documents, Congressional Sales Office, Washington, DC 20402 ISBN 0-16-060615-2 COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS JAMES M. JEFFORDS, Vermont, Chairman JUDD GREGG, New Hampshire EDWARD M. KENNEDY, Massachusetts BILL FRIST, Tennessee CHRISTOPHER J. DODD, Connecticut MIKE DeWINE, Ohio TOM HARKIN, Iowa MICHAEL B. ENZI, Wyoming BARBARA A. MIKULSKI, Maryland TIM HUTCHINSON, Arkansas JEFF BINGAMAN, New Mexico SUSAN M. COLLINS, Maine PAUL D. WELLSTONE, Minnesota SAM BROWNBACK, Kansas PATTY MURRAY, Washington CHUCK HAGEL, Nebraska JACK REED, Rhode Island JEFF SESSIONS, Alabama MARK E. POWDEN, Staff Director SUSAN K. HATTAN, Deputy Staff Director J. MICHAEL MYERS, Minority Staff Director and Chief Counsel SUBCOMMITTEE ON PUBLIC HEALTH BILL FRIST, Tennessee, Chairman JUDD GREGG, New Hampshire EDWARD M. KENNEDY, Massachusetts MICHAEL B. ENZI, Wyoming TOM HARKIN, Iowa SUSAN M. COLLINS, Maine BARBARA A. MIKULSKI, Maryland SAM BROWNBACK, Kansas JEFF BINGAMAN, New Mexico JEFF SESSIONS, Alabama JACK REED, Rhode Island JAMES M. JEFFORDS, Vermont (Ex Officio) ANNE E. PHELPS, Staff Director DAVID NEXON, Minority Staff Director (II) WELLCOME LIBRARY iGce neral Collections a. EA LIT Ne PYIKG S 2501827592 ‘ Denice TSH Oe Geeeaceaar STATEMENTS WEDNESDAY, FEBRUARY 2, 2000 Frist, Hon. Bill, chairman of the subcommittee, opening statement .................. Kennedy, Hon. Edward M., a U.S. Senator from the State of Massachusetts, Opening statement <3 ss. 2 6S Fc. Peery h APE reo. Be week ahaa ono rensorys et ersieens: Hutchinson, Hon. Tim, a U.S. Senator from the State of Arkansas, opening SERCO TMENS Utena cet seo doves Seek opceaetieaaseroa tice natn>bccus otepace sce tects siege ossise banker meee ee mee Te Bingaman, Hon. Jeff, a U.S. Senator from the State of New Mexico, opening BeR ORNCT N Ga nag acy ANN AG oo i tig Sect enna csenastbarsccenagerantosapunets=surnee s Gelsinger, Paul, Tucson, AZ, father of Jesse Gelsinger, participant in gene therapy; and Eric Kast, Norman, OK, on behalf of the Cystic Fibrosis phGae P OL Nene 8 he PAE Ae, Se gc ae Ree Oy me Pe ee = fee, Prepared statements of: BES Ea a 81202 a ec AE AN ae OE ER a ale ep HE RR oR VO EYo ra AR as APNE TAN wal Pee eee eo eee deer ease resus eee sess ESOS HESS ETOR OSES EL OS ESESES OS ESEEEDE SOOO ESSE STEED BESS ES EEEEEEE EE ESS RIESEC US UEC IDEN isp oon cos costae Ae ede aon heats Lsecvaneadatase cit ERE. AOE Patterson, Dr. Amy, Director, Office of Biotechnology Activities, National Institutes of Health, Bethesda, MD; and Dr. Jay P. Siegel, Director, Office of Therapeutic Research and Review, Food and Drug Administration, Rock- VL Sree teeta cee ee eee ee OE, Nena cloak oot s Pec svsdaevencbessseedersesnansesots Prepared statements of: Dee a GLO SR OT aie sot OF cca ened > cca saree sso es sans tewennasde <entsoncaht damian cesonins AB Re NTS eS, AR SR es eet Darras Ritts be ier ap atria an eps ion Me dh cp ee eth Verma, Inder, professor of molecular biology, Laboratory of Genetics, the Salk Institute, La Jolla, CA; Leroy Walters, director, Kennedy Institute of Ethics, Georgetown University, Washington, DC; and H. Stewart Parker, president and CEO, Targeted Genetics Corporation, Seattle, WA , on behalf of the Biotechnology Industry Organization ..0................eeesceceecececeeeeeecceeeseeeseeees Prepared statements of: . Introgen Therapeutics, Inc., prepared statement ...0.............-cceseeccecesenenseceeeeeeseeees Citizens For Responsible Care & Research, Vera Hassner Sharav, president & cofounder and Adil E. Shamoo, Ph.D., vice president & cofounder, pre- PIAELU SUHLCTINETIG: Soo ccuoterccccarneeigar tens cee Tecan cree Pte ns sb Tides sd a Nb ADDITIONAL MATERIAL Articles, publications, letters, etc.: Frist, Hon. William, chairman, Subcommittee on Public Health, from Judith Rodin, president, University of Pennsylvania, dated January Bie 8 Sp ee eres ety> teen demote cet Tenth RN atte te Meter eee fe 25 Gene Therapy in the United States: A Five-Year Status Report, by Gail Ross, Robert Erickson, Debra Knorr, Arno G. Motulsky, Robertson Parkman, Jude Samulski, Stephen E. Straus, and Brian Smith, from Human Gene Therapy, September 10, 1996 ...........eccccccccesessseeeceeseseceesees A Look At . . . Informed Consent, A Lot of Rules, Too Many Exceptions, by Abbey SaMeyers: 10. marcia io eli ine l, bene n-gececran Subcommittee on Public Health, from Bill Freese, dated February 8, AMIEL 2 det cnes velc eeg ard en ae UReS ones anctae vont at rereeateee eeates eet ee ae ese eee Frist, Hon. William, chairman, Subcommittee on Public Health, from William N. Kelley, M.D., ceo, University of Pennsylvania Medical Cen- ter and Health System, dated February 4, 2000 .............eccecccecceesseeeteeeees (1) aTMaMatare mas | Pee ene \ ¥ ‘ a +? 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WEDNESDAY, FEBRUARY 2, 2000 U.S. SENATE, SUBCOMMITTEE ON PUBLIC HEALTH, OF THE COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS, Washington, DC. The subcommittee met, pursuant to notice, at 9:35 a.m., in room SD-—430, Dirksen Senate Office Building, Senator Frist (chairman of the subcommittee) presiding. Present: Senators Frist, Jeffords, Hutchinson, Kennedy, Binga- man, and Dodd. OPENING STATEMENT OF SENATOR FRIST Senator FRIST. Good morning and welcome, everyone, to today’s hearing on what are truly critical issues regarding the subject of patient safety in gene therapy clinical trials. The events of the past few months involving gene therapy research have given all of us, our Government and our society, rea- son to pause and have prompted the subcommittee today to under- take and initiate a thorough review of this truly revolutionary research field and the systems that surround it. Today’s hearing is a very important one. We will be talking about death, we will talking about life. We will be talking about promising new research that could not have even possibly been imagined 30 years ago. We will be talking about the tough ethical issues such as informed consent and what conflict of interests exist. with the research community. We will be talking about the nature of experimentation in human beings—inherently risky, fundamentally profound. We will be talking about gene therapy, what is gene therapy, how does it differ from other therapy, and what promise does it hold for each of us and for our children. Gene therapy is an experimental procedure whose effectiveness has not yet been demonstrated, but it does offer real hope and real promise for those people who are suffering from genetic and nongenetic diseases. It holds great promise, but because it is experimental, there is an absolute necessity that we in Government and in the private sector provide appropriate and vigilant oversight. If we ask patients to participate in clinical trials to more promising science forward, we must assure them that their safety is first and foremost. I hope that today’s hearing will be a thoughtful discussion and will provide a thorough review of the oversight mechanisms that (1) 2 are in place, both in place on paper as well as giving us the opportunity to see whether what is on paper is actually being carried out. Doctors and scientists do have what I regard as a truly noble journey to pass along promising research and to explore that research in an appropriate way in this new scientific field. But in that journey, there is absolutely no place for mistakes that com- promise patient safety. The tragic death of Jesse Gelsinger, who was the first patient we learned about who died from gene therapy, has sombered us all. Jesse, as all of you know, was 18 years old. He had a rare liver disease. He unselfishly volunteered for a gene therapy clinical trial which was designed not to cure him but to develop a treatment that others, children and babies, could benefit from in the future. Mr. Paul Gelsinger, Jesse’s father, has generously agreed to be with us here today, and we offer our deepest condolences to the Gelsinger family and our true gratitude that he comes before us at a painful time in his own life to share with us his experience and to help us learn how we can make the big picture better and make the system better. As we will hear Mr. Gelsinger graphically de- scribe today, we absolutely must chart a new path that ensures that no family will have to endure what he and his family have had to endure over the last several months. Yet I predict that in the future, we are going to continue to learn more about adverse events that have occurred in gene therapy trials. Just this week, we have learned about more unreported deaths. The National Institutes of Health, who is with us today, following Jesse Gelsinger’s death put out a far-reaching call for all investigators conducting gene therapy research to remind them that they must report serious adverse events to NIH and to the FDA. The fact that NIH received 652 previously unreported serious adverse events in response to this request is really inexcusable. Clearly, our oversight system is failing. Our hearing today is the first step in the congressional examina- tion of the oversight procedures and guidelines in place at the NIH and the FDA to determine whether we have adequate systems to approve and then monitor these revolutionary new gene therapy trials. If we learn that the appropriate systems and guidelines are in place, on paper, we must then ask are they working in reality. I suspect they are not. The deaths of several patients reported over the last several days and the 652 previously unreported adverse events suggest the system is not working. All of these events trigger serious questions regarding Federal oversight of these gene therapy trials as well as adherence to the Federal guidelines that are out there on the part of the individual investigators themselves and the research community. So much of science today, at the pace at which it is moving, is introducing new ethical questions that we as policymakers must address—ethical questions regarding the risk to patients in human experimentation in these trials and the high financial interests iat are at stake as increasingly the private sector is funding such trials. We must examine our process of informing patients—is it time for us to go back and look at what truly informed consent means 3 in this new era of rapidly advancing science, and what constitutes truthful and complete information to patients. We must ask if there is an atmosphere of unrealistic expectations with regard to gene therapy, and we will talk about that with our third panel. What does gene therapy truly hold as a promise for cures for diseases, and how quickly can we realize those promises? Are patients given full information regarding past adverse events as they enter these clinical trials? My objective as we go forward is to keep the hearings balanced and to make sure that our discussion is careful. Nobody is on trial here—not the Government, not universities, not research scientists. It is clearly to everyone’s advantage to put everything on the table in as quick a fashion as we can. It is tough, because every day, new information is coming out, but I am very hopeful that over the course of this morning, we can achieve a balanced and careful ex- amination and discussion. We know that we can learn from previous mistakes. But we do need to know what those mistakes are if we are going to learn from them and if we are going to improve the system and if we are going to move forward in this field of gene therapy. The tragedy of Jesse Gelsinger should not result in another tragedy, and that other tragedy would be to bring a halt to this promising research. That is not the objective, and in fact, I feel strongly that we need to develop a system in which we allow this promising research to continue and to flourish. I believe it does have the potential of treating cancer and AIDS and cystic fibrosis and genetic and nongenetic diseases alike. Yet throughout, we must remain steadfast in our commitment to ensure that patients are safe, that there are adequate human protections in place, and that the research is meaningful and substantial. With that as an overview and before turning to Senator Ken- nedy, let me just tell people how I would like the hearing to go forward today. We will have opening statements, then we will have brief opening remarks from our witnesses. We have three panels today, and witnesses are asked to keep their remarks to around 5 to 6 minutes in length so we can carry on a dialogue among members and witnesses. Following the witness presentations, each of the Members will be allowed to ask questions. The hearing record will remain open for individuals who would like to submit no more than 10 double-spaced pages of written testimony until February 9, at which time the hearing record will be closed. Senator Kennedy. OPENING STATEMENT OF SENATOR KENNEDY Senator KENNEDY. Thank you, Senator Frist, and thank you very much for having these hearings. As you have mentioned, this issue is of critical importance to the Nation. No other medical technology offers greater potential to provide needed cures for so many diseases, and at the same time, no other medical technology has illustrated more clearly the need to protect patient safety and to provide the opportunity for informed consent. The tragic death of Jesse Gelsinger reminds us of the hope felt by those who look to gene therapy for a cure of their illnesses and 4 the need for constant watchfulness in protecting the safety of patients involved in medical research. In many ways, Jesse Gelsinger was a typical teenager. He loved motorcycles and professional wrestling; he spent time with friends and worked at the local grocery store. Yet in one respect, he was very different from all of his friends—not because he had a rare genetic disorder, but because he had the courage to put himself at risk to test what he deeply believed to be the best hope of a cure for those with genetic disorders. Tragically, Jesse’s courage led to his death. We must do all we can to see that Jesse’s sacrifice was not in vain. His hope was that someday, gene therapy would provide cures to the tens of thousands of babies born with genetic disorders every year and for the millions more affected by cancer, heart disease, AIDS and many other serious illnesses. The promise of gene therapy is shared by thousands of patients and is daily being brought closer to reality by talented researchers across the country. Today we will hear about some of the ways in which gene researchers are making gene therapy safer and more effective than it has ever been before. Our challenge is to see that those who volunteer to participate in gene therapy trials are fully protected from unnecessary risk. Oversight of this field should be as comprehensive as possible. In particular, when tragic events do occur, they must be reported in a timely way to the appropriate oversight agencies. We must also see that those who volunteer to serve as research subjects are fully informed of the possible risks of the treatment they are about to receive so that the consent they give is well-informed. I look forward to the testimony of our witnesses and to working with the members of the committee to assess the adequacy of the current rules governing this extraordinary area of medical research. We are particularly indebted to Mr. Paul Gelsinger for being here today and thank him for his own courage. It is never easy to talk about this kind of extraordinary human tragedy, and we are very, very grateful to him for being willing to appear before the committee today. Thank you, Mr. Chairman. Senator FRIST. Thank you, Senator Kennedy. Senator Hutchinson. OPENING STATEMENT OF SENATOR HUTCHINSON Senator HUTCHINSON. Thank you, Mr. Chairman. I think Senator Frist and Senator Kennedy have outlined the issues very clearly and very well. I just want to say, Mr. Gelsinger, that I was deeply moved as I read your testimony, and I look forward to hearing your testimony and your story. I noted in your written testimony you say that one of the leaders in the field called your son’s death “a pot-hole in the race to gene therapy,” and you observe that the concern should not be on get- ting to the finish line first but on making sure that no unnecessary risks are taken and no lives filled with potential and promise are lost forever. 5 How true, and I want to join Senator Kennedy in saying that in fact your son’s death was not in vain, and I think that already it has called the Nation’s attention to some very great dangers. So I appreciate your courage and your willingness to come forward today. I thank you for the hearing, Mr. Chairman. Senator FRIST. Thank you. Senator Bingaman. OPENING STATEMENT OF SENATOR BINGAMAN Senator BINGAMAN. Mr. Chairman, you and Senator Kennedy and Senator Hutchinson have outlined the issues. I thank you for having the hearing, and [I thank Mr. Gelsinger and the other witnesses for being here, and I look forward to the testimony. Senator FRIST. Thank you. Senator FRIST. Our first panel will discuss patient safety concerns and informed consent issues in clinical research. Mr. Paul Gelsinger of Tucson, AZ is the father of Jesse Gelsinger, who tragically passed away last September during par- ticipation in a gene therapy trial at the University of Pennsylvania. Mr. Eric Kast of Norman, OK—welcome, Mr. Kast—is a cystic fibrosis patient who has participated in a number of clinical trials, including a gene therapy trial, in order to contribute to the search for a cure for cystic fibrosis. He currently works for Blue Cross/ Blue Shield of South Carolina, where he educates medical equip- ment suppliers about Medicare claims. He received his bachelor’s and master’s degree in journalism and public relations from the University of Oklahoma. He is testifying on behalf of the Cystic Fi- brosis Foundation. Mr. Kast, again, thank you for being with us today and for your dedication in combatting a disease that we have made tremendous progress on over the last 15 or 20 years. We will begin with Mr. Gelsinger, who will be followed by Mr. st. STATEMENTS OF PAUL GELSINGER, TUCSON, AZ, FATHER OF JESSE GELSINGER, PARTICIPANT IN GENE THERAPY TRIAL; AND ERIC KAST, NORMAN, OK, ON BEHALF OF THE CYSTIC FIBROSIS FOUNDATION. Mr. GELSINGER. Thank you, Senator Frist, and thank you mem- Dens of this panel for allowing me to contribute to this hearing today. I am addressing this committee in the hope of bringing to light some very serious concerns that I have as a result of my son’s death. My son, Jesse Gelsinger, was participating in a first phase clinical trial conducted by the Institute for Human Gene Therapy at the University of Pennsylvania in Philadelphia. Jesse was recruited to participate in the trial after being told that his efforts would benefit newborns and other children with this specific disorder—ornithine transcarbamylase deficiency syn- drome—and for a myriad of other liver disorders. Jesse did not need to participate in this clinical trial; indeed, he was told that the trial would not benefit him in the least. At the time, Jesse was doing exceptionally well on his medications, and 6 nothine should have prevented him from living a full and happy ife. : He believed after discussions with the representatives from Penn that the worst that could happen in the trial would be that he would have flu-like symptoms for a week. He was also told that the most dangerous part of the procedure was to be the catheterization procedure by which the gene therapy would be introduced to his liver and the liver biopsy that was to be done a week later. With the knowledge I had at that time, I was comfortable enough to send my son, just 18 on June 18, 1999, to Philadelphia alone on September 9th to participate in this clinical trial. I was scheduled to fly to Philadelphia on September 18th to be present for the liver biopsy and to bring Jesse home. Jesse put his personal life aside, took an unpaid leave of absence from his job and accommodated everyone else’s schedule to do what he did. He was excited to help. In addition, Jesse relied on my judgment in participating in this clinical trial, and I trusted this to be a well-controlled and purely ethical effort. Less than 24 hours after they injected Jesse with the vector in an amount only one other person had ever been given, Jesse’s en- tire body began reacting adversely. He went into a coma before I could get to Philadelphia to see him and died 2 days after my arriv- al, directly as a result of that gene therapy experiment. While his death has been a devastating blow to us, his example has sustained us through it all. As you can imagine, my family and I have many concerns over what happened to Jesse. Jesse and I were told in late July 1999 that a prior patient—the patient before him—had shown a clinical improvement of 50 percent in her ability to eliminate ammonia from her system following gene therapy. At the Recombinant DNA Advisory Committee meeting in December, I discovered that no ef- ficacy was achieved at all in this patient. We were also unaware of the severity of liver injury incurred by several patients prior to Jesse. I learned after Jesse’s death that Penn had removed from the information they gave Jesse and me any reference to deaths of monkeys which had previously appeared in their documents. At the RAC meeting in December, I also learned that at least one other monkey died in:a related study using the same adenoviral vector used on Jesse. I learned that Penn neglected to follow its own and FDA’s proto- cols when it found that Jesse had ammonia levels above the per- missible limits—a clear danger sign—and yet went forward with the procedure anyway. I learned that a pharmaceutical company had conducted experi- ments similar to the one Jesse was in and had obtained adverse results which, if disclosed, would have fully informed Jesse and me of the real risks in this procedure. I had very close contact with the doctors involved until December 10, 1999, immediately following the RAC meeting. Looking back, I can see that I was very naive to have been as trusting as I was. As serious as my concerns are with the Penn trial as Jesse’s father, I have equally great concerns regarding the Federal oversight of gene therapy as an American citizen. As a result of Jesse’s death, many important issues regarding gene therapy have come to