<DOC> [109th Congress House Hearings] [From the U.S. Government Printing Office via GPO Access] [DOCID: f:30412.wais] HUMAN TISSUE SAMPLES: NIH RESEARCH POLICIES AND PRACTICES HEARINGS BEFORE THE SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS OF THE COMMITTEE ON ENERGY AND COMMERCE HOUSE OF REPRESENTATIVES ONE HUNDRED NINTH CONGRESS SECOND SESSION JUNE 13 AND JUNE 14, 2006 Serial No. 109-119 Printed for the use of the Committee on Energy and Commerce Available via the World Wide Web: http://www.access.gpo.gov/congress/house U.S. GOVERNMENT PRINTING OFFICE 30-412 WASHINGTON : 2006 _____________________________________________________________________________ For sale by the Superintendent of Documents, U.S. Government Printing Office Internet: bookstore.gpo.gov Phone: toll free (866) 512-1800; DC area (202) 512-1800 Fax: (202) 512-2250 Mail: Stop SSOP, Washington, DC 20402-0001 COMMITTEE ON ENERGY AND COMMERCE JOE BARTON, Texas, Chairman RALPH M. HALL, Texas JOHN D. DINGELL, Michigan MICHAEL BILIRAKIS, Florida Ranking Member Vice Chairman HENRY A. WAXMAN, California FRED UPTON, Michigan EDWARD J. MARKEY, Massachusetts CLIFF STEARNS, Florida RICK BOUCHER, Virginia PAUL E. GILLMOR, Ohio EDOLPHUS TOWNS, New York NATHAN DEAL, Georgia FRANK PALLONE, JR., New Jersey ED WHITFIELD, Kentucky SHERROD BROWN, Ohio CHARLIE NORWOOD, Georgia BART GORDON, Tennessee BARBARA CUBIN, Wyoming BOBBY L. RUSH, Illinois JOHN SHIMKUS, Illinois ANNA G. ESHOO, California HEATHER WILSON, New Mexico BART STUPAK, Michigan JOHN B. SHADEGG, Arizona ELIOT L. ENGEL, New York CHARLES W. "CHIP" PICKERING, Mississippi ALBERT R. WYNN, Maryland Vice Chairman GENE GREEN, Texas VITO FOSSELLA, New York TED STRICKLAND, Ohio ROY BLUNT, Missouri DIANA DEGETTE, Colorado STEVE BUYER, Indiana LOIS CAPPS, California GEORGE RADANOVICH, California MIKE DOYLE, Pennsylvania CHARLES F. BASS, New Hampshire TOM ALLEN, Maine JOSEPH R. PITTS, Pennsylvania JIM DAVIS, Florida MARY BONO, California JAN SCHAKOWSKY, Illinois GREG WALDEN, Oregon HILDA L. SOLIS, California LEE TERRY, Nebraska CHARLES A. GONZALEZ, Texas MIKE FERGUSON, New Jersey JAY INSLEE, Washington MIKE ROGERS, Michigan TAMMY BALDWIN, Wisconsin C.L. "BUTCH" OTTER, Idaho MIKE ROSS, Arkansas SUE MYRICK, North Carolina JOHN SULLIVAN, Oklahoma TIM MURPHY, Pennsylvania MICHAEL C. BURGESS, Texas MARSHA BLACKBURN, Tennessee BUD ALBRIGHT, Staff Director DAVID CAVICKE, General Counsel REID P. F. STUNTZ, Minority Staff Director and Chief Counsel SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS ED WHITFIELD, Kentucky, Chairman CLIFF STEARNS, Florida BART STUPAK, Michigan CHARLES W. "CHIP" PICKERING, Mississippi Ranking Member CHARLES F. BASS, New Hampshire DIANA DEGETTE, Colorado GREG WALDEN, Oregon JAN SCHAKOWSKY, Illinois MIKE FERGUSON, New Jersey JAY INSLEE, Washington MICHAEL C. BURGESS, Texas TAMMY BALDWIN, Wisconsin MARSHA BLACKBURN, Tennessee HENRY A. WAXMAN, California JOE BARTON, Texas JOHN D. DINGELL, Michigan (EX OFFICIO) (EX OFFICIO) CONTENTS Page Hearings held: June 13, 2006 1 June 14, 2006 205 Testimony of: Molchan, M.D., Susan, Program Director, AD Neuroimaging Initiative, Neuroscience and Neuropsychology of Aging Program, National Institute on Aging, National Institutes of Health, U.S. Department of Health and Human Services 167 Insel, M.D., Thomas R., Director, National Institute of Mental Health, National Institutes of Health, U.S. Department of Health and Human Services 208 Friedman, Ph.D., David L. 212 Gottesman, M.D., Michael M., Deputy Director of Intramural Research, National Institutes of Health, U.S. Department of Health and Human Services 257 Additional material submitted for the record: Insel, M.D., Thomas R., Director, National Institute of Mental Health, National Institutes of Health, U.S. Department of Health and Human Services, response for the record 276 Fitzsimmons, William, Executive Officer, National Institute of Mental Health, National Institutes of Health, U.S. Department of Health and Human Services, response for the record 279 Gottesman, M.D., Michael M., Deputy Director of Intramural Research, National Institutes of Health, U.S. Department of Health and Human Services, response for the record 284 Friedman, Ph.D., David L, response for the record 288 HUMAN TISSUE SAMPLES: NIH RESEARCH POLICIES AND PRACTICES TUESDAY, JUNE 13, 2006 HOUSE OF REPRESENTATIVES, COMMITTEE ON ENERGY AND COMMERCE, SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS, Washington, DC. The subcommittee met, pursuant to notice, at 2:04 p.m., in Room 2123 of the Rayburn House Office Building, Hon. Ed Whitfield (Chairman) presiding. Members present: Representatives Stearns, Walden, Burgess, Blackburn, Barton (ex officio), Stupak, Baldwin, and Whitfield. Staff present: Mark Paoletta, Chief Counsel for Oversight and Investigations; Alan Slobodin, Deputy Chief Counsel for Oversight and Investigations; Mike Abraham, Legislative Clerk, Ryan Ambrose, Legislative Clerk; John Ford, Minority Counsel; Jessica McNiece, Minority Research Assistant; and William Garner, Minority Professional Staff Member. MR. WHITFIELD. I would like to call this hearing to order this afternoon. Today and tomorrow, the subcommittee examines the important issue of human tissue samples. These samples, such as blood, cells, and spinal fluid are raw material of biomedical research that can help improve our healthcare. These samples matter because of their growing importance in biomedical research. Detailed genetic and other biological marker information can be derived from these samples and with such information, we can dramatically improve the way we diagnose and treat disease. The National Institutes of Health is at the forefront in collecting these samples and using them for unique medical research not conducted in universities or industrial labs. NIH scientists obtain these samples through a great deal of care and work with patients and healthy volunteers who participate in biomedical experiments. The ability of NIH researchers to obtain samples from people and the resources and the freedom to research relies on a basic trust. These hearings focus on whether that trust used to obtain human samples for research at NIH is working as well as it should. We look at this important question through the prism of a case study. The study involves Dr. Trey Sunderland of the National Institute of Mental Health, and the vials of human spinal fluid and plasma he shipped to Pfizer from 1998 to 2004. Some members of the subcommittee may recall Dr. Sunderland's name from the subcommittee's June 2004 hearing, where we revealed the discrepancies between information provided by Pfizer documenting over $500,000 in outside consulting payments to Dr. Sunderland over a 5-year period, and the information that was given to NIH and to the committee showing no documentation of disclosure or approval of these very same outside consulting activities for Dr. Sunderland. NIH has investigated these discrepancies and made its determination of multiple violations of legal and ethical requirements. But today's inquiry is about an investigation beyond those compliance issues. We are concerned primarily about the integrity of NIH research. The committee's concerns in this area were prompted in part by Dr. Susan Molchan, who is the Program Director for Alzheimer's disease research at the National Institute of Aging. From 1993 to 1995, she conducted a small clinical trial involving the collection of spinal fluid from about 25 people, some patients with Alzheimer's disease and some normal volunteers, and used lithium as a probe for potential biomarkers of Alzheimer's disease in spinal fluid and blood. She had published two papers and told the committee staff that she had used, at the very most, 20 percent of the spinal fluid collected. The unused spinal fluid remains stored in freezers at NIMH geriatric/psychiatric branch. The chief of the geriatric/psychiatric branch, Dr. Trey Sutherland, assumed control of the spinal fluid and the samples after Dr. Molchan left. In the fall of 2004, Dr. Molchan was at the NIA and was trying to assist an outside researcher in getting unused samples from Dr. Molchan's unfinished study. Ultimately by March of 2005, she learned that Dr. Sunderland was only able to produce a very small percent of the unused spinal fluid that remained from her lithium study, and that the clinical data from that study had been purged. She was concerned about what happened to the more than 95 percent of the unused spinal fluid samples left in the freezer and to the data. She pursued her concerns for several weeks during 2005 through various NIH channels and with the Office of Inspector General, Department of Health and Human Services as well. In April 2005, she contacted staff with the Committee on Energy and Commerce. After more preliminary work from the committee staff, the bipartisan leadership of the committee and the subcommittee started a broad investigation on the issue of human tissue samples at the National Institutes of Health and the particular case involving Dr. Sunderland and the spinal fluid samples. The committee has been investigating this issue for over a year now. We have requested records and information. After reviewing the records and interviewing people, the committee staff assembled evidence in its report for the subcommittee members. The report, which will be placed in the hearing record, raises some very troubling questions. Dr. Sunderland is a leading researcher in the area of Alzheimer's disease. For years, he has been interested in finding a diagnostic test for this disease. Pfizer was also interested in this goal, and this joint interest was worthy of a scientific collaboration between government and the private sector. In 1998, Dr. Sunderland had an opportunity to pursue this project legitimately with Pfizer and a British biotechnology firm under existing laws and policies that promote this public/private partnership. Instead, disappointingly, the evidence shows that Dr. Sunderland used his public office to provide spinal fluid and plasma samples to Pfizer at the same time that he engaged in personal consulting with Pfizer about these very same samples. He did not disclose these consulting arrangements to NIH; this subcommittee exposed them. And even after he was under investigation, the records show that Dr. Sunderland did not accurately describe the nature of his consulting activities with Pfizer. According to the records obtained by the committee, Dr. Sunderland provided over 3,000 spinal fluid and plasma samples to Pfizer and received $285,000 from Pfizer for two different projects using these samples. Congress and NIH have provided the proper mechanisms for government/industry partnership and we encourage it. Federal laws and policies do not permit, however, NIH scientists to profit personally from their jobs and their patients by providing irreplaceable government assets. Unfortunately, the evidence before us shows Dr. Sunderland operated outside that system. Why did he choose to enrich himself? There were mechanisms available to get the resources for his lab as part of this collaboration, but there are not records that we have been able to find or information showing that this was done, and why not? There were mechanisms available to him and NIH scientists to obtain patents and royalties. Dr. Sunderland, however, assigned his patent rights to Pfizer under one of the two research projects and he was listed as a co-inventor at his home address. Why didn't he tell NIH? Why didn't he protect the rights of NIH? And what about the Alzheimer's disease patients and human volunteers who had their spines punctured and then had to lie on their sides for three hours after each procedure? Did Dr. Sunderland tell them he was going to make money from their spinal fluid, and why did he make a statement and reaffirm to NIH investigators that his outside activities were with one part of Pfizer and that the material transfer agreement, his official activities in providing the samples were with another part of Pfizer, when the same Pfizer official signed the consulting agreement and the material transfer agreement? Why did Dr. Sunderland, who has an excellent reputation as a researcher and is considered beyond reproach as the Chairman for 10 years of NIH's Institutional Review Board put himself in the position of being under investigation? In learning more about the circumstances of Dr. Sunderland's conduct, the committee's investigation uncovered other serious questions about the adequacy of NIH policy and oversight regarding human tissue samples. For example, Dr. Sunderland transferred the human tissue samples taken from subjects for a new research purpose without consulting with NIH officials or even the Institutional Review Board in charge of protecting these samples. Is that a violation of ethical rules, or is that an acceptable practice? From the available evidence, Dr. Sunderland alone, it appears, decided to transfer a large number of human tissue samples to Pfizer, a company in which he had a financial consulting interest. But would Alzheimer's disease research have been better served if Dr. Sunderland had consulted with the other NIH experts and tested the samples, not just with the technology involved in the Pfizer projects, but with other technologies with other companies as well? We hope to gain more insight to these matters and improve the operations of NIH for the benefit of the American people. Already, this investigation has led NIH to revise informed consent requirements and has helped stimulate discussions within the Institutes to improve policies related to human tissue samples. Some of the concerns raised have also led to the Institutes making new inquiries about human subject protection and assignment of patent rights involved in the Dr. Sunderland matter. Today, we will have one witness, and that is Dr. Susan Molchan, who helped raise these concerns over human tissue samples, and then tomorrow we will have witnesses from NIH, including the Deputy Director of Intramural Research, a former Pfizer scientist who worked with Dr. Sunderland, an associate of Dr. Sunderland's involved in the Pfizer activities. I want to thank Chairman Barton for his support of this investigation, and Mr. Dingell and Mr. Stupak for their support, and we look forward to Dr. Molchan's testimony. [The prepared statement of Hon. Ed Whitfield follows:] THE PREPARED STATEMENT OF THE HON. ED WHITFIELD, CHAIRMAN, SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS Today and tomorrow, the Subcommittee examines the increasingly important issue of human tissue samples. These samples - such as blood, cells, and spinal fluid - are the raw material of biomedical research that can help improve our healthcare. These samples matter because of their growing importance in biomedical research. Detailed genetic and other biological marker information can be derived from these samples. With such information, we could dramatically improve the way we diagnose and treat disease. The National Institutes of Health (NIH) is at the forefront in collecting these samples and using them for unique medical research not conducted in university or industry labs. NIH scientists obtain these samples through a great deal of care and work with patients and healthy volunteers who participate in biomedical experiments. The ability of NIH researchers to get samples from people and the resources and the freedom to research relies on trust. These hearings focus on whether that system of trust behind the human samples research at NIH is working as well as it could. We look at this important question through the prism of a case study - an approach this Subcommittee uses often in its oversight hearings. The case study involves Dr. Trey Sunderland of the National Institute of Mental Health (NIMH) and the vials of human spinal fluid and plasma he shipped to Pfizer from 1998 to 2004. Some members of the Subcommittee may recall Dr. Sunderland's name from the Subcommittee's June 2004 hearing where we revealed the discrepancies between information provided by Pfizer documenting over $500,000 in outside consulting payments to Dr. Sunderland over a five-year period and the information given by NIH to the Committee showing no documentation of disclosure and approval of these very same outside consulting activities for Dr. Sunderland. NIH has investigated these discrepancies and made its determination of multiple violations of legal and ethical requirements. But today's inquiry is about an investigation beyond these compliance issues. We are concerned about the integrity of NIH research. The Committee's concerns in this area were prompted in part by Dr. Susan Molchan, Program Director for Alzheimer's Disease Research at the National Institute of Aging (NIA). From 1993 to 1995, she conducted a small clinical trial involving the collection of spinal fluid from about 25 people (some patients with Alzheimer's disease and some normal volunteers) and the use of lithium as a probe for potential biomarkers of Alzheimer's disease in spinal fluid and blood. In early 1997, Dr. Molchan left the NIMH, but she had not finished this study. She had published two papers and told the Committee staff that she had used at the very most 20% of the spinal fluid collected. The unused spinal fluid remained stored in freezers at the NIMH Geriatric Psychiatry Branch. The Chief of the Geriatric Psychiatry Branch, Dr. Trey Sunderland, assumed control of the spinal fluid samples after Dr. Molchan left NIMH. In the fall of 2004 Dr. Molchan was at the NIA and was trying to assist an outside researcher in getting unused samples from Dr. Molchan's unfinished study held at NIMH. Ultimately by March 2005, Dr. Molchan learned that Dr. Sunderland was only able to produce a small percent of unused spinal fluid that remained from the lithium study and that the clinical data from that study had been purged. (SLIDE 4) She was concerned about what happened to the more than 95% of the unused spinal fluid samples left in the freezer and to the data. She pursued her concerns for several weeks during March- April 2005 through various NIH channels and with the Office of Inspector General (OIG), Department of Health and Human Services (HHS). In April 2005 she contacted staff with the Committee on Energy and Commerce. After more preliminary work from the Committee staff, the bipartisan leadership of the Committee and the Subcommittee started a broad investigation on the issue of human tissue samples at NIH and the particular case study involving Dr. Sunderland and the spinal fluid samples. The Committee has been investigating this matter for a year. We requested records and information. After reviewing the records and interviewing people, the Committee staff assembled evidence in its report for the Subcommittee members. The report - which will be placed in the hearing record -- raises some troubling questions. Dr. Sunderland is a leading researcher in the area of Alzheimer's disease. For years, he had been interested in finding a diagnostic test for this disease. Pfizer was also interested in this goal. This joint interest was worthy of a scientific collaboration between government and the private sector. In 1998 Dr. Sunderland had an opportunity to pursue this project legitimately with Pfizer and a British biotechnology firm under existing laws and policies that promote public-private partnerships. Instead, the evidence shows that Dr. Sunderland used his public office to provide spinal fluid and plasma samples to Pfizer. At the same time, Dr. Sunderland engaged in personal consulting with Pfizer about these very same samples. He did not disclose these consulting arrangements to NIH - this Subcommittee exposed them. Ever after he was under investigation, the records show that Dr. Sunderland did not accurately describe the nature of his Pfizer consulting activities to NIH. According to the records obtained by the Committee, Dr. Sunderland provided over 3,000 spinal fluid and plasma samples to Pfizer (SLIDE 5) and received $285,000 from Pfizer for two different projects using these samples. (SLIDES 1 and 2) The Congress and NIH have provided the proper mechanisms for government-industry partnerships. Federal laws and policies do not permit NIH scientists to profit personally from their jobs and their patients by providing irreplaceable government assets. Unfortunately, the evidence before us shows Dr. Sunderland operated outside that system. Why did he choose to enrich himself? There were mechanisms available to get resources for his lab as part of this collaboration. But there are no records or information showing this was done. Why not? There were mechanisms available to him and NIH scientists to get patents and royalties. Dr. Sunderland, however, assigned his patent rights to Pfizer under one of the two research projects and he was listed as a co-inventor at his home address. Why didn't he tell NIH? Why didn't he protect the rights of NIH? What about the Alzheimer's disease patients and human volunteers who had their spines punctured and then had to lie on their sides for three hours afterward? Did Dr. Sunderland tell them he was going to make money from their spinal fluid? Why did Dr. Sunderland make a statement and reaffirm to NIH investigators that his outside activities were with one part of Pfizer, and that the material transfer agreement, his official activities in providing the samples, were with another part of Pfizer when the same Pfizer official signed Dr. Sunderland's consulting agreements and the material transfer agreement? Why did Dr. Sunderland - who had an excellent reputation as a researcher and was considered beyond reproach as the Chairman for 10 years of NIMH's Institutional Review Board - put himself in the position of being under investigation? In learning more about the circumstances of Dr. Sunderland's conduct, the Committee's investigation uncovered other serious questions about the adequacy of NIH policy and oversight regarding human tissue samples. For example, Dr. Sunderland transferred the human tissue samples taken from human subjects for a new research purpose without any consultation with NIH officials or the Institutional Review Board in charge of protecting human subjects. Is that a violation of ethical rules or acceptable practice? From the available evidence, Dr. Sunderland alone decided to transfer a large number of human tissue samples to Pfizer, a company in which he had a financial consulting interest. But would Alzheimer's disease research have been better served if Dr. Sunderland had consulted with other NIH experts and tested the samples not just with the technology involved in the Pfizer projects but with other technologies with other companies? We aim at these hearings to gain more insight into these matters and improve the operations of NIH for the benefit of the American people. Already this investigation has led NIH to revise informed consent requirements and has helped stimulate discussions within NIH to improve policies related to human tissue samples. Some of the concerns raised have also led to NIH making new inquiries about human subject protection and assignment of patent rights involved in the Dr. Sunderland matter. Today we will hear from Dr. Susan Molchan who helped raise the concerns over human tissue samples. Tomorrow, we will have witnesses from NIH including the Deputy Director for Intramural Research, a former Pfizer scientist who worked with Dr. Sunderland, an associate of Dr. Sunderland involved in the Pfizer activities, and Dr. Sunderland himself. I want to thank Chairman Barton for his support of this investigation. I also want to thank Mr. Dingell and Mr. Stupak for their support of this investigation. I also want to note that Pfizer was cooperative with the Committee's investigation and we appreciate that. I look forward to hearing from the witnesses. MR. WHITFIELD. At this time, I recognize Mr. Stupak. MR. STUPAK. Thank you, Mr. Chairman, and thanks for holding this hearing today. We are going to have another one tomorrow. This inquiry has been a bipartisan effort for the past year. The staff report released today provides the committee with a sound basis to do our work. I compliment the bipartisan committee staff work and their report. Through no fault of our staff, I do note that this investigation took much longer than should have been necessary. The National Institutes of Health and/or its overseers at the Department of Health and Human Services apparently had a hard time understanding our bipartisan request letter. Like other initial inquiries from the committee, they originally treated our request like a nuisance, something to respond to in a perfunctory way. For instance, instead of supplying the committee with documents showing the disposition of the specific spinal fluid samples as requested, NIH gave us unsatisfactory excuses, such as possible freezer failure. We subsequently learned that NIH had records of the samples we requested, which were among 3,300 tubes of fluid samples shipped to Pfizer. In the 2004 conflicts of interest investigation, the subcommittee discovered that about 100 NIH scientists failed to report income from the 20 drug companies that the committee had surveyed. Pfizer and other drug companies had the records; of course, NIH did not. Fortunately for this investigation, when we could not get the records of samples shipped out of the National Institute of Mental Health lab, Pfizer again had the records. I find it very disturbing that Pfizer has kept better records than NIH. Interestingly, both of these investigations touched on a specific National Institute of Mental Health lab chief, Dr. Trey Sunderland. Only after this subcommittee provided this information to NIH 2 years ago did NIH become aware of Dr. Sunderland's receiving over $500,000 from Pfizer without reporting it. Yet, when we requested an accounting of the human tissue samples in Dr. Sunderland's control, NIH officials apparently accepted his explanation that such records did not exist. This represents a complete lack of due diligence and negligence on the part of NIH. Unfortunately, the performance of the Department of Health and Human Services Inspector General, was similarly lacking. Because there is an ongoing inquiry, we will delay the examination of the performance of those investigators, but our preliminary information is that this IG continues to ignore its first responsibility, which is to keep the Department clean. Mr. Chairman, the NIH has much to account for today. Priceless human tissues samples, samples from a unique collection that is not likely to be replicated, even at NIH, were shipped without any authority, any oversight, any accountability for a private research effort that was evaluated by a single government employee. That employee was Dr. Sunderland, a lab chief who, in the end, would pocket $285,000 from his decisions. We estimate that those samples cost NIH over $6 million, and took 15 years to collect. As you noted, Mr. Chairman, spinal fluid is not easy to obtain. It involves three or more hours of inconvenience and often considerable pain for each volunteer on each occasion. People volunteered those samples to advance Alzheimer's research, most often because they or their loved ones suffered from this disease. The volunteers trusted the judgment that NIH would put their samples to best use. Unfortunately, NIH's failure to supervise its employees permitted a single scientist to make the judgment to give away irreplaceable samples. The lack of oversight also allowed Dr. Sunderland to take some 140 days of travel to perform his Pfizer consults. The failure to demand accountability allowed one of the two corroborative research projects to proceed without any protection of NIH's right to the resulting data or right to intellectual property resulting from the research. As a result, Pfizer owns all research products. Of course, NIH didn't know any of this until we asked, because they have no uniform audit policy for acquisition, use, and/or storage of human tissue samples; storage and protection of data generated by their research; determination of whether human subject protection and informed consent are assured after any specific protocol is ended; accounting for leave of senior employees; assuring that the appropriate legal instruments are used when human tissues are transferred; or accounting for the fruits of corroborative research data and patents. Mr. Chairman, it is time to rectify the inadequate oversight that has enabled these reckless activities to occur. Congress entrusts NIH with billions of dollars each year. Biomedical research needs to be guided by an unbiased assessment of producing strategies for diagnosis or treatment, not whether an NIH researcher maximizes his or her personal gain. Furthermore, thousands of Americans entrust NIH with their personal medical histories, tissue samples, and other information each year to help find cures for diseases. We need to honor their commitment by ensuring that the highest scientific standards are upheld. Mr. Chairman, I yield back the balance of my time. MR. WHITFIELD. Thank you, Mr. Stupak. At this time, I will recognize the gentleman from Texas, Dr. Burgess. MR. STUPAK. Mr. Chairman, if I may, before Dr. Burgess, I ask unanimous consent to enter into the record the statement of Mr. Dingell, the Ranking Member of this committee. Thank you. [The prepared statement of Hon. John D. Dingell follows:] THE PREPARED STATEMENT OF THE HON. JOHN D. DINGELL, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF MICHIGAN Mr. Chairman, thank you for holding this hearing and initiating this bipartisan investigation. This inquiry is an example of how productive oversight can be when it is truly bipartisan. And it has been bipartisan from the first Chairman's letter to the staff report we have before us today. You and Representative Stupak have worked together and our staffs have worked together each step of the way. What have we uncovered? For one thing a number of serious deficiencies in individual National Institutes of Health (NIH) processes that are enumerated in the staff report. No one looks to see if priceless human tissue samples are being put to their best use. No one is looking to see if human subject protection rules are followed. No one has to account for his or her time or budget. Trusting scientific decisions to the scientists is one thing. Giving carte blanche to individual researchers to spend funds and divert precious human tissue resources derived from patients under their care is quite another. Congress has taken the approach that biomedical research decisions are best left to the scientists. This is as it should be. We owe it to the taxpayers, however, to ensure that the scientists who make decisions regarding very expensive life and death research options do so in a rational manner with accountability at least within the scientific community. These investigations and the conflict of interest hearings held in 2004 have exposed a severe structural weakness in the oversight functions within NIH. First it was ethics, now it is something even broader. Dr. Zerhouni did a good job tightening up the ethical environment after our last set of hearings. I hope Dr. Gottesman will undertake a similar clean-up campaign designed to return accountability to this great institution. MR. BURGESS. Thank you, Mr. Chairman, and thank you for your continued leadership in the investigation that has become another very important public health issue. During my tenure in Congress, I have had the privilege of visiting the National Institutes of Health several times. After each visit, I come away encouraged; encouraged by the research and the studies that the scientists perform on a daily basis. After each visit, my hope that a cure for cancer, a cure for Alzheimer's will be found, if not during my lifetime, then perhaps during the lifetime of my children. I would like to take this opportunity to sincerely thank the doctors, researchers, and scientists at the National Institutes of Health for their dedication to such a noble profession. It is my opinion that outside consulting by scientists is not within itself an unethical practice. While outside consulting is currently prohibited by NIH employees, I believe that these types of arrangements can be beneficial to society as a whole if constructed in an ethical and transparent manner. The situation before us involving Dr. Sunderland is an egregious example of how the system can fail if there is lack of transparency and a lack of ethical behavior. Dr. Molchan, thank you for bringing this situation to our attention. In preparation for today's hearing, the committee released a bipartisan staff report to the members of this subcommittee. I think it is important to note that the bipartisan staff report came to a concluding paragraph, and I am quoting here, "It should be noted that the committee staff found no evidence that Pfizer had any knowledge relating to the questionable conduct of Dr. Sunderland in connection with the April, 1998, material transfer agreement and subsequent shipments of samples." The unethical practice lies clearly and solely with Dr. Sunderland. Congress continues our work on reauthorization of the National Institutes of Health, a program that spends almost $30 billion a year, and it is money well spent. I feel certain that we can use the lessons learned today and tomorrow throughout the reauthorization process. It is our role to provide adequate oversight over the National Institutes of Health and ensure that taxpayer dollars and other resources, including tissue samples, are used in a worthwhile and ethical manner. We must not abrogate our responsibility to the American public regarding this important task. Mr. Chairman, again I thank you for holding this hearing, and look forward to a lively discussion on the procedures concerning human tissue samples. I will yield back the balance of my time. MR. WHITFIELD. Thank you, Dr. Burgess, and I would, without objection, want to enter into the record the staff report on this entire issue, as well as those slides and the exhibits. Without objection, so ordered. [The information follows:] A STAFF REPORT For the Use of the Subcommittee on Oversight and Investigations In Preparation for Its Hearing, "Human Tissue Samples: NIH Research Policies and Practices," June 13-14, 2006 This staff report was written by the Majority and Minority Committee staff of the House Committee on Energy and Commerce. Background Human tissues are biological materials defined as "including everything from subcellular structures like DNA, to cells, tissue (bone, muscle, connective tissue, and skin), organs (e.g., liver, bladder, heart, kidney), blood, gametes (sperm and ova), embryos, fetal tissue, and waste (urine, feces, sweat, hair and nail clippings, shed epithelial cells, placenta)." For purposes of the Subcommittee's inquiry, this report focuses on biological materials most frequently used in biomedical research such as tissues and cells. These are raw biological materials extracted from human beings that are to be distinguished from the biological inventions derived from such samples. These extracted tissues are stored and generate portions of tissues called samples. Ever since 1858 when Rudolf Virchow wrote his famous book that detailed how changes in cells accounted for diseases in organs, human tissue samples have been the foundation of biomedical research. In its 1999 report, the RAND Corporation published a "conservative estimate" that more than 307 million tissue samples from more than 178 million people were stored in the United States. This number was reportedly increasing by more than 20 million samples a year. Tissue samples have played a central role in major studies such as the Framingham studies on heart disease and the Women's Health Initiative (WHI), one of the largest women's health studies in which over a 15-year period, 161,000 women gave blood, urine, and other samples to investigators. Human tissue samples also have significant value to biotechnology and pharmaceutical companies because these materials "can help them: reduce drug development times; develop new therapies and drugs; react quickly to unexpected adverse reactions; and identify new assay techniques or biomarkers." The issue of human tissue samples has assumed greater importance at the National Institutes of Health (NIH) and strengthened the need for more guidance to NIH-funded institutions (NIH's extramural research program that are more than 80 percent of the NIH's budget) as well as for the Institutes and Centers at the NIH that conduct their own research (NIH's intramural research program). As noted by the NIH's Director of the Office of Science Policy to NIH staff: "[H]uman specimen repositories and the use of human specimens and data are becoming an increasingly important part of our efforts to advance basic science research and translate discoveries into improved medical care. However, the lack of consistency in the regulations, policies and procedures governing this type of research is creating confusion and barriers for researchers, repository managers, IRB [Institutional Review Board] staff, and their institutions. The magnitude of these challenges will likely grow as advances in informatics make it possible to make human datasets of unprecedented size and scope widely available to the research community." In response to these perceived challenges and as part of the NIH Roadmap, the NIH is coordinating "a high priority effort to develop trans-NIH policies to govern NIH funded research with human specimens and data and to work across government to promote more consistent policies in this area." The focus of the inquiry for this hearing is the collection, storage, tracking, and use of human tissue samples in the NIH intramural research program. The Committee's investigation in this area was prompted in part by concerns raised by Susan Molchan, M.D., Program Director for Alzheimer's Disease Research at the National Institute of Aging (NIA), to Committee staff in April 2005. Dr. Molchan had been a clinical researcher interested in Alzheimer's disease research at the National Institute of Mental Health (NIMH). From 1993 to 1995, she conducted a small clinical trial involving the collection of spinal fluid from about 25 people (some patients with Alzheimer's disease and some normal volunteers) and the use of lithium as a probe for potential biomarkers of Alzheimer's disease in spinal fluid and blood. In early 1997, Dr. Molchan left the NIMH, but she had not finished this study. She had published two papers and used at the very most 20 percent of the spinal fluid collected. The unused spinal fluid remained stored in freezers at the NIMH Geriatric Psychiatry Branch. The Chief of the Geriatric Psychiatry Branch was Trey Sunderland, M.D., who assumed control of the spinal fluid samples after Dr. Molchan left NIMH. At a hearing on June 22, 2004, the Subcommittee on Oversight and Investigations revealed that Dr. Sunderland had received over $500,000 in payments from Pfizer during 1999-2004 for outside consulting and speaking without any record of prior approval for these activities or disclosure in his government financial-report filings. By the fall of 2004, Dr. Molchan had been back at the NIH for three years, this time at the National Institute of Aging. At a meeting of top scientists and researchers, she learned that an outside researcher was pursuing funding for a lithium study similar to the one that Dr. Molchan had been unable to complete at NIMH. Spinal fluid samples are extremely valuable and very difficult to obtain. The outside researcher was very interested in getting Dr. Molchan's assistance in obtaining the spinal fluid samples and the linked clinical data from her study. Dr. Molchan agreed to assist. In the fall of 2004, Dr. Molchan asked Dr. Sunderland about the samples. After two months of inquiries, Dr. Sunderland sent two 0.5 cc samples from 10 subjects (about 2-3 percent of the unused amount of spinal fluid) to the outside researcher. In March 2005, Dr. Molchan asked Dr. Sunderland about the linked clinical data. Dr. Sunderland told her that that the data had been purged because it was over 5-7 years old and subject to purging. Dr. Molchan was concerned about what happened to the more than 95 percent of the unused spinal fluid samples left in the freezer and to the data. In particular, after the public reports about Dr. Sunderland's undisclosed activities with Pfizer, she was concerned that Dr. Sunderland might have inappropriately or improperly diverted spinal fluid samples from her lithium study to Pfizer as part of his financial relationship. She pursued her concerns for several weeks during March-April 2005 through various NIH channels and with the Office of Inspector General (OIG), Department of Health and Human Services (HHS). In April 2005 she contacted staff with the Committee on Energy and Commerce. In investigating her concerns and in general about the relevant NIH policies, the Committee staff learned from NIH officials that NIH had no uniform, centralized, and mandatory authority regulating the handling of human tissue samples. Some NIH laboratories kept a written record on the maintenance of these samples, but other NIH laboratories did not. Although there were explicit regulations defined in 42 C.F.R. 72.6 detailing the handling for hazardous biological materials and select agents, there was no explicit policy for the handling and accounting of human tissue samples. In addition, there was no formal inventory control or tracking system at NIH. If a freezer or other storage facility malfunctions and the human tissue samples become unusable, NIH laboratories were not required to account for the disposition of these samples. There was reason to believe that there were cases where NIH lost human tissue samples but had no record of what had been lost. Moreover, the lack of accountability left NIH wholly vulnerable to theft and diversion of valuable human tissue samples. These preliminary inquiries raised serious concerns over what was described to Committee staff by NIH officials as a fairly loose, ad-hoc approach to controlling human tissue samples. On June 20, 2005, the bipartisan leadership of the full Committee and the Subcommittee sent a letter to the Director of the NIH requesting records and information on how human tissue samples are obtained, stored, tracked, and used in intramural programs throughout the institutes and centers of the NIH. In the context of this investigation, the Committee focused primarily on spinal fluid samples and blood samples obtained from patients and other people participating in NIH intramural clinical trials. One subject area of the Committee's June 20, 2005, request concerned the disposition of spinal fluid samples from patients with Alzheimer's disease and control subjects collected by scientists at the National Institute of Mental Health (NIMH) to be used in studies involving lithium. After the NIH's August 15, 2005, production, the Committee staff alerted the NIH that it appeared that not all responsive documents concerning these samples and Dr. Molchan's lithium study had been provided to the Committee. After the Committee staff raised these concerns with NIH about the production, the Committee did receive additional responsive records: three sets of records over the last few months from the NIH related to the spinal fluid samples and the lithium study, with the last set received on January 4, 2006. The Committee was troubled that the NIH did not produce all the responsive records in the first production, and produced these records only after Committee staff pressed several times for these additional responsive records. Most importantly, an NIH document received by the Committee in early 2006 documented that the Geriatric Psychiatry Branch (GPB) had sent spinal fluid samples to Pfizer from 538 subjects, who had participated in 14 different studies at NIMH. (See Exhibit 26) The protocol numbers listed on the documents showed that spinal fluid had been sent to Pfizer from subjects who had participated in Dr. Molchan's lithium study. That fact had not been previously disclosed to either Dr. Molchan or to the Committee. On January 24, 2006, the bipartisan leadership of the Committee and the Subcommittee sent a letter to NIH requesting additional records about the disposition of the spinal fluid samples, the nature of NIMH oversight over human samples, and the way NIH/NIMH handled the Committee's request for records relating to the lithium study. In addition, on January 24, 2006, the bipartisan leadership of the Committee and the Subcommittee sent a letter to Pfizer, requesting records that could help determine the relationship, if any, between the disposition of the spinal fluid samples in question and Dr. Sunderland's official and/or private consulting activities with Pfizer. Methodology To review these issues related to human tissue samples, the Committee staff conducted extensive interviews with officials from NIH, former officials with NIH, officials with Pfizer, former officials with Pfizer, and other individuals. Staff reviewed documents obtained by the Committee from NIH and Pfizer. Staff also reviewed public information and records. NIH's Internal Investigation The NIH's Office of Management Assessment (OMA) conducted an internal investigation of Dr. Sunderland's outside activity discrepancies first revealed in substantial part at the Subcommittee's June 22, 2004, hearing. The OMA found that Dr. Sunderland engaged in serious misconduct, in violation of HHS ethics rules and Federal law and regulation. The OMA confirmed that there was no documentation for Dr. Sunderland seeking prior approval or reporting the Pfizer activities. After the revelations of the Pfizer activities, Dr. Sunderland self-reported additional activities with other drug or biotech companies that lacked required documentation in which his payments almost totaled $200,000. Dr. Sunderland claimed that these were paperwork violations and that his outside activities did not constitute conflicts of interest with his official duties. In particular, Dr. Sunderland contended that his outside consulting did not relate to his official duty collaboration with Pfizer, which involved the sharing of spinal fluid samples under an April 1998 Material Transfer Agreement (MTA). However, the Ethics Review Panel convened by NIH in April 2005 found a direct overlap between the subject matter of Dr. Sunderland's official area of research and the scientific subject matter of his Pfizer consultancies. In addition, the Panel expressed concern over the 1998 MTA that Dr. Sunderland entered into with Pfizer while he maintained an ongoing consulting relationship with the company in the same area. In addition, in a memorandum dated October 12, 2005, the NIH Ethics Panel found that Dr. Sunderland's official duties constituted an overlap with some of unapproved outside activities with other drug companies he self-reported. (Exhibit 35) On September 24, 2004, NIH referred an allegation to the Office of Inspector General - HHS (OIG) that Dr. Sunderland may have conducted outside activities during Government work hours without charging leave. Other records in connection with Dr. Sunderland beyond the issue in the referral have also been forwarded by NIH to the OIG. Committee's Investigation It should be noted that the NIH investigated Dr. Sunderland's failure to obtain prior approval and disclose outside activities. NIH did not investigate the details of the underlying outside activities at issue. The concerns raised about human tissue samples led the Committee to investigate issues that arose from Dr. Sunderland's transfers of human tissue samples to Pfizer and examined the details of Dr. Sunderland's two principal consulting arrangements with Pfizer. This staff report is a preliminary report to assist the Members of the Subcommittee on Oversight and Investigations in preparing for the hearings to be held on June 13 and 14, 2006. Question One: Did Dr. Sunderland obtain personal financial benefits from outside activities (with no record of disclosure to NIH or approval by NIH) with Pfizer, Inc., in any way because of actions he took in his official capacity in facilitating the transfer to Pfizer of human spinal-fluid samples and plasma samples, which were the assets and property of NIH? Finding/Supporting Evidence: Yes. Records and interviews provide reasonable grounds to believe that Dr. Sunderland personally received $285,000 in compensation from Pfizer for activities that were derived directly from his official acts in providing Pfizer access to spinal fluid samples and plasma samples (over 3000 tubes of NIH property and linked clinical data) and that Dr. Sunderland used NIH employees and resources to provide such access. Discussion: The Committee's inquiry focused on the consulting agreements involving Dr. Sunderland's collaborations with Pfizer using human tissue samples procured from his Geriatric Psychiatry Branch in the National Institute of Mental Health (NIMH). Records from Pfizer show that the transfer of spinal fluid samples from Dr. Sunderland's branch at NIMH to Pfizer under an April 1998 Material Transfer Agreement coincided with the initiation of a two-year consulting agreement related to Dr. Sunderland's advice on information generated from those samples. The MTA and the consulting agreement were part of the same scientific collaboration. This consulting agreement and a spin-off consulting agreement from the collaboration netted Dr. Sunderland a minimum of $25,000 per year plus $2,500 per day for each one- day meeting (1998-2003). According to Pfizer, payments under these two contracts totaled $285,000, exclusive of reimbursement of travel expenses. Dr. Sunderland had been collecting human tissue samples and the related clinical information from NIH Alzheimer's disease patients and their families and controls since the early 1980s. This longitudinal collection of spinal fluid and blood samples was unique. While it was possible to purchase spinal fluid samples from Alzheimer's disease patients, individuals interviewed by Committee confirmed it was unlikely that anywhere but at the clinics of NIH could this unique historical collection of human tissue samples be assembled. Dr. Sunderland collected not only human tissue samples from Alzheimer's disease patients but also samples from their blood relatives as well as samples from controls. The longitudinal aspect included in this collection gave the samples their unique character. At least some of the subjects had samples drawn both before and after the onset of Alzheimer's disease. Interviews and records obtained from Pfizer provide reasonable grounds to believe that obtaining these spinal fluid samples together with their clinical histories was a primary reason for Pfizer's interest in collaborating with Dr. Sunderland. The samples themselves and the linked clinical data associated with these samples are generally considered to be valuable assets because such samples can be used for diagnostic, therapeutic, research, and commercial purposes. NIH has told the Committee that it takes the position that tissue samples are the property of the U.S. Government to the extent that NIH asserts an exclusive right to control the disposition and distribution of that material. That would seem to be the case where the NIH has exclusive possession and control of the samples through its storage of these materials in its freezers in its own buildings, all funded by U.S. taxpayers. NIH continually asserts its ownership interests in such samples through its technology transfer policies and legal contracts such as Material Transfer Agreements (MTAs) and Cooperative Research and Development Agreements (CRADAs). In addition, the NIH-1884 form "Request for shipment" used to ship tissue samples to Pfizer noted that they were shipments of government-owned property. (See Exhibit 22) Three legal documents were involved in the transfer of invaluable human tissue samples and the collaborative research that resulted: a material transfer agreement (MTA) between NIH and Pfizer signed by Dr. Trey Sunderland and two consulting contracts between Pfizer and Dr. Sunderland. A material transfer agreement is to be distinguished from a collaborative research and development agreement (CRADA) and a consulting agreement involving the scientist and a company independent of the NIH. In a scientific endeavor such as the Pfizer/Sunderland collaboration, according to some NIH officials interviewed by Committee staff, a CRADA would have been the appropriate legal umbrella for this kind of research. (This is discussed in more detail later in this report.) Not only would that arrangement spell out the contributions and obligations of both parties, but it also would spell out the distribution of data and intellectual property rights between the government and the private sector firm, in this case Pfizer. Had a CRADA been negotiated, Dr. Sunderland would not have been able to receive any outside income for his efforts in the collaboration as it would have been part of his official duties. Although NIH policies on technology transfer mechanisms were evolving and unclear in 1998, according to an NIH official interviewed by Committee staff, because the transfer involved a commercial entity, it is unlikely Pfizer could have taken possession of the samples of this value without a document authorizing the transfer. Absent a CRADA, an MTA was the instrument that specified the terms under which the NIH would release human tissue samples for a specific research purpose. The MTA did not obligate Pfizer to share the resulting data with NIH nor did it specify that the government retained any intellectual property right to the fruits of the proposed research. Based on its past investigations of NIH scientists' outside consulting agreements, Committee staff believes that Pfizer would not have entered into a scientific collaboration with Dr. Sunderland or any other scientist without a private contract that contained two critical clauses: confidentiality and the right of Pfizer to all intellectual property created as a result of the collaboration. In a CRADA, Pfizer would not have retained exclusive rights to the data or any patents. Dr. Sunderland would have been precluded from any outside income from the collaboration, if there had been a CRADA such as the one he had executed with Abbott Labs in 1989 in transferring 115 spinal fluid samples. (Exhibit 28) In this regard it is important to note that Dr. Sunderland is listed as a co-inventor with Pfizer researchers on patents filed in Europe and here in the US relating to the April 1998 MTA. (Exhibit 29) Dr. Sunderland executed at least one assignment of his patent rights to Pfizer as did his co-inventors as was required by his contract of June 10, 1998, and as is typical of discoveries made while on a private payroll. (Exhibit 30) The United States is not an assignee. In 1997 Pfizer entered into a collaboration with a British firm, Oxford Glycosciences (OGS), to identify unknown biomarkers that would signal the onset of Alzheimer's disease using a proprietary OGS proteomics technology. Dr. David Friedman, the lead Pfizer researcher on the project, began courting Dr. Trey Sunderland in an attempt to obtain access to the NIH human tissue samples in the fall of 1997. In his interview with Committee staff, Dr. Friedman said he came to understand the significance of the depth of Dr. Sunderland's expertise in his early discussions. On February 20, 1998, Dr. Friedman, and three other Pfizer scientists visited Sunderland's lab at NIMH. A Pfizer e-mail documenting the visit stated: "In discussions regarding Pfizer's needs and Sunderland's needs, Trey indicated that he was very happy with an MTA arrangement plus consulting that Kathy [Smith] has been discussing. Trey was also very interested in publication in a reasonable time frame and that he wanted to make sure that authorship would be based on scientific and intellectual contributions. We indicated agreement on both matters." A month later, at the suggestion of Dr. Sunderland, Kathryn Monaghan (now Smith), a Pfizer manager, called Kathy Conn, the tech transfer official at NIMH, about using an MTA to transfer spinal fluid samples. Ms. Monaghan believed that this phone call reflected NIH's agreement to proceed with the material transfer agreement and that they can "work out the CRADA vs. Consult part in due course." (Exhibit 31) On April 6, 1998 Kathy Monaghan faxed the final version of the MTA to Dr. Sunderland and informed him that the deal with OGS had been finalized. (Exhibit 2) However, Ms. Conn informed the Committee staff that she was unaware that the final MTA had been executed. Records and Committee staff interviews of the individuals involved revealed that neither the Director of NIMH nor the NIMH Scientific Director, the two supervisors of Dr. Sunderland, had knowledge of the transfer of the uniquely valuable samples or were informed of the MTA negotiations. On April 8, 1998, Dr. Sunderland signed the MTA to transfer coded clinical samples of spinal fluid and the accompanying data from over 250 subjects to Pfizer. Six days later, Dr. Barrie Hesp signed the MTA for Pfizer. In a letter dated April 20, 1998, Pfizer sent Dr. Sunderland at NIH the signed copy of the MTA with a note that indicated that they expected the samples to be shipped mid-May (Exhibit 1) Dr. Sunderland was then sent a "draft consulting agreement" to his home in a letter dated on the same day. (Exhibit 5) A two-year consulting agreement that Pfizer labeled the "OGS" agreement was signed by Dr. Hesp (dated June 10, 1998) and Dr. Sunderland (dated June 18, 1998) effective May 1, 1998. (Exhibit 7) It provided for a consulting payment to Dr. Trey Sunderland of $25,000 per year and $2,500 per day for each meeting plus expenses. This agreement was renewable for two-year periods, and was renewed two more times. It should be noted that this consulting agreement required that Dr. Sunderland transfer any interest he may have in the research arising from the agreement with Pfizer as he subsequently did with the patent assignment. (Exhibit 7) Dr. Sunderland also agreed not to "disclose confidential information for so long as it remains unpublished." Only after the consulting agreement was signed were the samples finally shipped from NIH. According to Dr. Friedman in his interview with Committee staff, on or around June 24, 1998, Drs. Friedman and Sunderland accompanied 621 tubes to OGS in Britain. But Dr. Sunderland did not deliver the clinical data associated with the samples until August 1998. Emails indicate Pfizer officials were quite upset about the delay because the associated clinical information made these samples useful for the intended research and this delay would affect the pace of the research. (Exhibit ). Pfizer calls this research project involving NIMH and OGS the "unknown biomarkers" project. By the end of July 1998, Pfizer and Sunderland decided to pursue a second collaboration regarding the validity of already "known biomarkers," a beta and tau. (Exhibit 8) The NIH spinal fluid samples were to be used for this project as well. This second project resulted in a second separate consulting agreement for Dr. Sunderland but not a new MTA for the transfer of NIH samples for this separate and new Pfizer research project. The second consulting agreement was signed by Dr. Hesp for Pfizer with an October 6, 1998, date and by Dr. Sunderland with an October 12, 1998, date. On February 9, 1999, the shipment of spinal fluid samples from NIH to Pfizer for the "known biomarkers" project began. According to records and information, approximately 3,200 tubes of spinal fluid and 388 tubes of plasma were shipped to Pfizer in connection with both biomarker projects. (See Slide 5) Of these, 2,200 or so were for the "known biomarkers" project and the remaining 1,100 were for the "unknown biomarkers" research. The spinal fluid samples linked with the well-characterized clinical data are invaluable tools for scientific research. Based on available records, the NIH only had data on the 2,132 tubes shipped in connection with the "known biomarkers" project. The Committee staff has reasonable grounds to conclude that NIH did not have knowledge of the more than 1,000 tubes of spinal fluid shipped pursuant to the "unknown biomarkers" agreement. Question Two: Does the available evidence provide reasonable grounds to believe that Dr. Sunderland and others omitted important information, or provided inaccurate information, about the circumstances surrounding Dr. Sunderland's collaborations with Pfizer, Inc. that involved the human samples provided by Dr. Sunderland? Finding/Supporting Evidence: Yes. While Dr. Sunderland refused invitations to be interviewed by the Committee, records and interviews provide reasonable grounds to believe that some of Dr. Sunderland's statements to the investigators from the Office of Management Assessment and communications from Dr. Sunderland's attorney to NIH were factually inaccurate or incomplete, especially statements relating to the nature of the Pfizer collaborations involving human tissue samples. Discussion: The Office of Management Assessment (OMA) of the NIH interviewed Dr. Sunderland regarding these matters on August 19, 2004. Dr. Sunderland signed the interview notes on August 31, 2004, confirming with an "X" that "[t]hese notes, with indicated changes, accurately summarize the interview." (Exhibit 14) Dr. Sunderland informed OMA that while he had taken the required ethics courses and understood there were rules governing disclosure of financial interests and approval of outside activities "he may not have paid proper attention" to such matters in the past. He maintained that he did provide the documents from which to complete the 520s (outside activity request forms) but that somehow the clerical staff did not make the necessary submissions nor did they inform him that such submissions were not made. With regard to his financial disclosure forms, Dr. Sunderland placed blame for at least part of their inaccuracy on his support staff. The OMA dismissed this argument: "Dr. Sunderland violated NIH and Commissioned Corps procedures and policies on multiple occasions (Pfizer reported 140 activities for which there were no approvals) all of which cannot be dismissed as administrative oversights or anomalies. Given that he acknowledges that he had concerns about administrative support, he should have ensured that forms were submitted to the NIMH ethics office and that approvals were given. Dr. Sunderland was aware of the NIH ethics process through ethics training and was ultimately responsible for ensuring that all activities were approved and all financial disclosures were made." (See Exhibit 32) Committee staff interviewed several individuals within the Geriatric Psychiatry Branch run by Dr. Sunderland and found no support for his position regarding clerical malfeasance. When asked about his consulting conflicts of interest, Dr. Sunderland told OMA that "he had a consulting arrangement with Pfizer Corporate and the MTA with Pfizer researchers." In fact, not only was the MTA and his initial consulting agreements signed by the same Pfizer official, Dr. Barrie Hesp, both contracts covered work directly related to the samples initially supplied under the MTA. (Exhibit 13) Dr. Sunderland further claimed that he sent human spinal fluid samples to Pfizer as he had to more than 30 other collaborators and that his collaboration with Pfizer would not have required visits to the company, as this was "an exchange of material for analytical data." In fact, records show that Dr. Sunderland and his associate Karen Putnam visited the Pfizer facilities on a number of occasions to work on the data and, according to Dr. Friedman, at least once Dr. Sunderland accompanied Friedman and the spinal fluid samples on a plane to OGS in England. In addition to the Friedman interview information and several e-mails discussing trips to Pfizer in relation to the unknown biomarker work, both Karen Putnam and Pfizer informed Committee staff that Pfizer considered the primary data associated with the unknown biomarker project to be proprietary and could only be accessed on Pfizer property. (Exhibit 33) Another inconsistency with the relevant documents and the information conveyed by Pfizer regarding Dr. Sunderland's consulting activities was Dr. Sunderland's statement in the OMA interview that "his consulting work with Pfizer has to do with drug development and lectures." Certainly lectures to audiences of doctors arranged by Pfizer's marketing team charged with promoting Aricept accounted for substantial payments to Dr. Sunderland ($311,150 from 1996 to 2004 according to Pfizer) (Exhibit 34) The consulting work involving the human tissue samples, however, was separate and apart from those lectures. (Exhibit 34) To the extent Dr. Sunderland meant that his "drug development" consulting was drug-specific, except perhaps for participation on various Pfizer-sponsored Advisory Boards relating to marketing strategy, Committee staff found little evidence from records or interviews that Dr. Sunderland's consulting with Pfizer was related to any existing drug or drug under development. On the other hand, if Dr. Sunderland meant that his "drug development" consulting in a more general way applying to strategic advice to classes of medications, his attorney in a December 8, 2004, letter to NIH distinguished this general consulting from his work on the "unknown biomarkers" project: "Generating new approaches to shorten the duration of clinical trials using various target markers is an obvious priority for companies like Pfizer, and Dr. Sunderland provided ongoing consultation about the development of such strategies. This consulting is quite different and separate from the exploration of peptide biomarkers for possible diagnostic and prognostic use in Alzheimer's disease." (Emphasis added). Later in the same letter, Dr. Sunderland's attorney described a reason for the April 1998 MTA collaboration as "[p]roteomic exploration of CSF [cerebrospinal fluid] was designed to help discover peptide targets for drug development with both scientific and potential commercial applications." (Emphasis added). During much of the time period (1998-2004) of Dr. Sunderland's consulting with Pfizer, Ms. Karen Putnam was a 32- hour per week employee of NIMH assigned to Dr. Sunderland's branch, although she was telecommuting from the University of Cincinnati where she was pursuing a graduate degree. (See Exhibit 11) According to e-mails, Dr. Sunderland urged Pfizer to hire Ms. Putnam to administer the database related to the unknown biomarker project. Pfizer tightly held the data from this "collaboration" so her work on that database had to be done at the company. Ms. Putnam performed a similar function with regard to the "known biomarkers" database. She informed the Committee staff that she understood that while the "unknown biomarkers" project was covered by her consulting agreement with Pfizer, the work she and Dr. Sunderland did with Pfizer on known biomarkers was a part of her official duties. Both biomarker projects started with consulting contracts between Pfizer and Dr. Sunderland, not independently and solely from NIH. During his OMA interview Dr. Sunderland was asked whether he told Karen Putnam that she did not have to seek approval for her work with him at Pfizer. In the signed interview notes Dr. Sunderland claimed not to remember if he told Ms. Putnam not to file, but he went on to state that he did not think she had to because she was a part-time employee on an IPA and because "her duties did not overlap with any decisions regarding drug or protocol development." Ms. Putnam was a direct report to Dr. Sunderland and had received almost $65,000 in consulting fees and expenses from Pfizer to manage the data of the unknown biomarker study. (Exhibit 39). OMA found, and Ms. Putnam confirmed, that she had not submitted requests for outside activities. Exhibit 11. In addition, the NIH ethics review panel concluded that had Karen Putnam filed a request for outside activity the request would have been denied because it related to her official duties. (Exhibit 27) OMA noted in its review of Karen Putnam's outside activities that in an e-mail to Ms. Putnam, dated June 18, 2004, the NIMH Ethics Coordinator stated that Dr. Sunderland had called from abroad to say that he had advised Ms. Putnam that she did not have to file for prior approval. Dr. Sunderland's attorney in an August 31, 2004, letter to OMA stated: "There was no conflict between his consulting/lecturing and his clinical work at the NIH. . . "[He] never hid that relationship; and that there never was a conflict of interest - in any respect whatsoever - between his NIH work and what he did as a consultant and speaker for Pfizer. . . . The relevant facts are now before the NIH in their entirety." The NIH Ethics Review Panel specifically found that there was "a direct overlap between the subject matter of Dr. Sunderland's official area of research and the scientific subject matter of his Pfizer consultancies." (Exhibit 35) He would not have been "given prior approval for the consultant activities." The Ethics Panel "expressed further concern over the Material Transfer Agreement (MTA) that Dr. Sunderland entered into with Pfizer in 1998 while he maintained an ongoing consulting relationship with the company in the same area." Based on records and interviews, Committee staff believes that NIH did not conduct interviews with Pfizer employees nor obtain from Pfizer the underlying records of Dr. Sunderland's consulting agreements. Thus, even without the Pfizer documents and interviews that show connections between the MTA and the consulting, the Ethics Review Panel still concluded in April 2005 that there was a conflict of interest. Moreover, OMA believed that Dr. Sunderland did much of the Pfizer-paid work on government time. Dr. Sunderland acknowledged in the OMA interview that he never kept track of his leave time nor, as her supervisor at NIH, did he check to see if Ms. Putnam had taken leave when he signed her time cards. Records and interviews also raised questions about Dr. Sunderland's openness about the "unknown biomarkers" consulting agreement involving a third-party British company called OGS. For example, in her June 9, 1998, e-mail, Kathryn Smith noted to other Pfizer officers: "For your information, Dr. Trey Sunderland at NIH (our source for the AD samples) has requested that we do not mention him in any publicity concerning his involvement in our OGS collaboration." (Exhibit 23). In addition, when the Committee first raised questions about the discrepancies involving Dr. Sunderland's outside activities with Pfizer, the NIMH ethics coordinator in a June 18, 2004 e-mail to Dr. Sunderland asked directly: "There is a record of an MTA agreement with Pfizer signed 4/98. Could payments have related to that?" (Exhibit 16) Based on records and interviews, there is no evidence that Dr. Sunderland responded to this question. It should also be noted that the terms of Dr. Sunderland's consulting agreements state: "Pfizer agrees that it will not make public this agreement nor the terms associated with it." Dr. Trey Sunderland is still an employee at the NIMH and is a member of Public Health Service Commissioned Corps. Administrative action rests with the Corps and not NIH per se. Dr. Thomas Insel, the Director of NIMH, forwarded a summary of the OMA findings and those of the Ethics Panel to the Commissioned Corps, noting that he was informed that civilian employees guilty of the same violations would be proposed for removal. In relevant part that document states: "Dr. Sunderland placed the NIH in a position where it had to respond to allegations of impropriety, which compromised faith in the Agency and trust in our research. Dr. Sunderland violated ethics rules with regard to his relationship with Pfizer and engaged in relationships with Pfizer and many other organizations that would not have been approved had he submitted them for approval in accordance with the process for seeking approval of outside activities...Not disclosing over $500,000 in income was not an oversight or lapse in judgment but appears to be a deliberate decision not to comply with the rules, policies and procedures that are necessary to protect the NIH, its scientists and most importantly, its science." Question Three: Did the Committee's investigation of the circumstances surrounding Dr. Sunderland's transfer of human samples to Pfizer identify evidence that raised other compliance issues and policy questions? Finding/ Supporting Evidence: Yes. The investigation found reasonable grounds to believe there was questionable compliance with human subject protection and NIH technology transfer policies that existed at the time. The evidence also raised regulatory and ethical questions that are pertinent to NIH's consideration of current policy related to human tissue samples. Discussion: Human subject protection A human subject is a living individual about whom a researcher (called an investigator) obtains either (1) data through intervention or interaction with the individual, or (2) identifiable private information. In the case study before the Subcommittee, Dr. Sunderland and other researchers collected spinal fluid by injecting the human subject with a needle at the base of the spine in a procedure called lumbar puncture (LP). According to the informed consent language in several of the protocols involved, this procedure is conducted in the morning, after the subject has had a night of bedrest. The subject lies on one side, the subject's lower back is cleaned with antiseptic, and a local anesthetic such as novocaine is injected in order to temporarily numb a small area of skin. A needle is then placed into the spinal fluid sac, allowing an ounce of spinal fluid to drip into collection tubes. The needle is then removed and the subject is asked to lie on her/his abdomen for three hours to reduce the likelihood of developing a headache after this procedure. The LP procedure only takes 5-15 minutes. Most subjects experience only minor or moderate pain, similar to that experienced when an injection is received. The spinal fluid samples, usually collected in 20-30 cc amounts, are then alliquotted or subdivided into ten smaller tubes. Some small subset of the total amount is then used for the research study, with several other vials or test tubes of fluid left over, unused, stored in -70 degree centigrade freezers. Researchers at the NIH are responsible for protecting the rights and welfare of the human subjects who participate in their research. All intramural researchers at the NIH are responsible for knowing whether or not their research involves human subjects. Thus, legal obligations to protect human subjects apply to human tissue samples and private information, such as medical information, that can be readily identified with individuals. a. Questionable handling of informed consent. One issue presented by this matter involves the adequacy of informed consent for new, future uses of leftover human samples. The ethical foundation for informed consent is the principle of respect for persons, which requires that research subjects be given the opportunity to choose what shall and shall not happen to them. Valid informed consent requires disclosure of relevant information about the research, comprehension of the information by the prospective subject, and his or her voluntary agreement, free of coercion and undue influence, to participation. In this case, Dr. Sunderland transferred spinal fluid samples to Pfizer that were collected from subjects whom most were told of the specific purpose of the particular research study being conducted, but not about the research purpose of the Pfizer collaboration, because in many cases that collaboration had not yet even been developed. At the time of collection, many of the spinal fluid samples were not obtained for the research purpose of the Pfizer collaboration. In general, there is a question about whether most of the protocols at issue had adequate informed consent language about consenting for future research uses of leftover samples. A few of the protocols involving the subjects are still ongoing and Dr. Sunderland actually sought Institutional Review Board (IRB) approval for amending these ongoing protocols to reflect the new research purpose involving Pfizer. Human subject protection regulations, however, state that unless the samples are anonymized and not linked to identifiable patients, the human tissue samples are not exempt from IRB review and some independent review (either from the IRB or the human subjects protection office of the institute or center) must be conducted to determine if full IRB review is needed and if so, whether the subjects need to be consented again for the new use. With respect to the samples transferred to Pfizer, NIH reported to Committee staff by e-mail that "[n]either the NIH OHSR [Office of Human Subjects Research] nor the NIMH [Institutional Review Board] have records documenting a review of the transfer to Pfizer." According to NIH, "Dr. Sunderland has advised NIH that he believed at the time of the transfer that use of specimens in his collaboration with Pfizer, as described in the 1998 MTA, was completely consistent with both the protocols in which those samples were obtained, and the informed consent documents signed by participants." But was it Dr. Sunderland's judgment alone to determine whether the use of the samples was consistent with the protocols? Under the April 1995 Guidelines for the Conduct of Research Involving Human Subjects in effect at the time of the 1998 transfer, the use of human tissue samples were exempt from the NIH requirements on human research protection if the sources of pathological specimens "cannot be identified directly or through identifiers linked to the subjects." The Guidelines also state in bolded print: "Investigators should not make determinations about exemptions without consulting OHSR." The terms of 1998 Material Transfer Agreement (Exhibits 2 and 3) and the records produced by Pfizer relating to the samples provide reasonable grounds to believe that Dr. Sunderland intended to transfer, and actually transferred, coded clinical samples to Pfizer. Coded clinical samples are specimens supplied with a code rather than a name or social security number. Because these samples remain linked through codes to identifiable subjects, questions are raised over whether these samples would have been covered by human subject protection guidelines and whether Dr. Sunderland should have sought an independent consultation or determination. Currently, in light of concerns raised by the Committee's investigation and at the direction of the NIH Deputy Director for Intramural Research, an NIH investigation is being conducted to determine if Dr. Sunderland violated any regulatory or ethical standards in transferring spinal fluid samples to Pfizer without any IRB review from protocols that did not cover the research purpose in the Pfizer biomarker projects. b. Inadvertent disclosure of subject names and other privacy information. In reviewing records produced by Pfizer, Committee staff found that February-March 1999 spreadsheet records for assays of two different potential biomarkers in 1999 contained the names of approximately 120 subjects who were the sources of the biological material, along with their codenames, NIH ID numbers, dates of birth, race, and sex. In consultation with Pfizer's outside counsel, Committee staff confirmed that these records did indeed represent an inadvertent disclosure of subject names. According to Pfizer's outside counsel in a March 31, 2006, letter to Committee staff, the spreadsheets contained information transcribed by Pfizer from labels on the vials sent by the NIMH. The samples were subsequently coded by Pfizer for analysis using the first three letters of the patient's last name followed by the first three letters of the first name. The results of the study were included in the April 23, 2003, article in the Journal of American Medical Association as well as the analysis of a later set of samples. Subsequent samples arrived from the NIMH pre- coded using a numerical coding system. In response to the Committee staff's question about Pfizer's handling of this inadvertent disclosure, Pfizer's outside counsel wrote: "At the time that the NIH disclosure occurred, the Health Insurance Portability and Accountability Act (HIPAA), which established requirements regarding the use and disclosure of Protected Health Information, was not yet in effect, and thus there was no legal obligation imposed upon Pfizer to return or reject the information received. Even under the current HIPAA requirements, Pfizer's research and development organization is not a 'covered entity,' and the duties imposed on such persons inadvertently receiving protected information are not clear. However, we believe Pfizer handled the inadvertent disclosure appropriately by creating an [sic] code to de-identify patients in the course of the research effort." There is no evidence that Pfizer contacted NIH about the inadvertent disclosure. There is no evidence that NIMH was aware of the inadvertent disclosure. If that was the case, NIH had no information to determine what led to the inadvertent disclosure, and was not in a position to correct a possibly recurring, systemic problem that increases the risk of inadvertent disclosure of privacy information. Further investigation would be needed to determine the circumstances that led to the inadvertent disclosure. Committee staff understands from a discussion with NIH Acting Director for Human Research Protection that the release of patient names, whether accidental or not, is not consistent with NIH research standards and any manuscript in connection with the affected research project might not be published. This would need to be reported to the IRB, and to the NIH Deputy Director for Intramural Research. The NIH Deputy Director in turn might report this disclosure to the Office of Human Research Protection. c. Questionable non-disclosure of financial relationship to IRB. As part of his financial arrangement with Pfizer, Dr. Sunderland transferred spinal fluid samples to Pfizer from 1998 to 2004 for which he was paid $285,000 to advise Pfizer on data relating to the samples provided. According to NIH records, Dr. Sunderland provided spinal fluid samples that had been collected from 14 different studies. Two of these studies were initiated in 2001 and 2002, respectively. In other words, Dr. Sunderland was performing lumbar punctures for spinal fluid at a time Pfizer wanted spinal fluid samples, and at a time Dr. Sunderland sought and received monetary compensation for his efforts to assist Pfizer in interpreting data generated from these spinal fluid samples he provided. In addition, while other studies no longer involved active collection of spinal fluid, these studies were still ongoing and were subject to continuing review by the NIMH IRB. As part of this continuing review process, Dr. Sunderland as the accountable investigator on the study had to check off "yes" or "no" responses to a series of questions on the NIH-1195 form, Clinical Research Protocol Continuing Review Application. The last question on the form was: "Have any investigators developed an equity or consultative relationship with a non-NIH source related to this protocol which might be considered a conflict of interest?" According to all forms related to spinal fluid protocols signed by Dr. Sunderland during the time he was consulting with Pfizer, the "no" box response was checked. (Exhibit 24) Committee staff did not receive any records that linked the individual samples provided to Pfizer to specific protocol numbers. The 2001 study and the 2002 study, however, were identified as sources of spinal fluid samples to Pfizer. (Exhibit 26) Thus, while the Committee staff does not believe it has records linking the protocol number to a particular NIMH shipment to Pfizer, samples were provided to Pfizer from these studies in one of those years in which Dr. Sunderland represented to the IRB that he (or any other investigator associated with the study) had no outside financial interests related to the protocol. d. Cancellation of lithium study without notice to subjects. Dr. Molchan left NIMH in early 1997. By that time, Dr. Molchan had completed the spinal fluid collection phase of the lithium study a few years earlier. She was still, however, conducting the study and had used only a relatively small percentage of the samples. Committee staff understands that sometimes when an NIH scientist in charge of a human subjects study leaves NIH, another NIH scientist is assigned to take charge of the study and the study is continued. When Dr. Molchan left NIMH, there was reason to believe (IRB approval, two papers published) the lithium study would be continued and that Dr. Sunderland as Branch Chief would either take over the study or assign someone to take over the study. Instead, the study was discontinued. Committee staff has asked NIH why the study was discontinued. To date, NIH has not provided a response on why this study was discontinued. Committee staff has not found any evidence that the subjects in the lithium study were notified about the termination of a study. In these cases, where a clinical trial is terminated, the question is raised whether the subjects in that study should be notified of the termination. It is unclear how common it is for the written protocols of the clinical trial to include provisions about termination and notification. On the question of when a subject should be notified about termination of a study, an NIH official with expertise on human subjects protection told Committee staff that she believed that it depended on whether the study followed the subjects over a period of time. Nevertheless, the NIH Office of Intramural Research is working on a computer consent prototype and whether it should be a standard requirement to inform subjects of a study's termination. Technology Transfer Issues In pursuing its mission, NIH scientists often discover new technologies. The process of sharing these new technologies with other organizations and the public is called technology transfer. For example, the sharing of new research materials with colleagues, the pursuit of collaborative relationships with outside entities, and the awarding of intellectual property rights to commercial entities for development and commercialization, are all considered technology transfer activities. The NIH Office of Technology Transfer is responsible for developing and implementing technology transfer policies at NIH. Each Institute has a technology transfer office that monitors, evaluates, and manages the Institute's invention portfolio. These offices review Employee Invention Reports (EIRs) and negotiate transactional agreements between the Institute and outside parties, including other Federal laboratories, State and local governments, universities, and pharmaceutical and biotechnology companies. Among these agreements are Material Transfer Agreements (MTAs) for the exchange of research materials, and Cooperative Research and Developments Agreements (CRADAs) for collaborative research endeavors. In this case, questions are raised in a number of areas about how NIMH at the time implemented technology transfer policies and the adequacy of certain technology transfer policies. a. Improperly authorized transfer. The transfer of spinal fluid samples was facilitated by the April 1998 Material Transfer Agreement between NIMH and Pfizer. The Committee's investigation found two versions of the executed MTA. One version contained the signature of Dr. Sunderland as the provider of the samples on behalf of NIMH and the signatory for Pfizer, Dr. Barrie Hesp. (Exhibit 3) This is the only version of the MTA that Pfizer told the Committee staff it has. Committee staff found no evidence that Pfizer had any other version of the MTA. According to a Pfizer manager involved with the MTA, Pfizer made an effort to confirm that Dr. Sunderland had the authority. A March 1998 Pfizer e-mail does substantiate phone contact between the Pfizer manager and the NIMH technology transfer director about the MTA. Although she did not have specific recollection about the Pfizer phone call, the NIMH technology transfer director at the time (who has since left the NIH) told the Committee staff that she recalled getting phone calls about MTAs. These would not have been calls to receive official clearance but just preliminary inquiries. These kinds of calls were not documented. According to the official, she believed the Pfizer inquiry would have been about what form to use in transferring samples to Pfizer. She did not know that Dr. Sunderland and Pfizer were executing the MTA immediately. She expected to see the MTA and review it. There is, however, no evidence showing she received any Pfizer correspondence and was sent the MTA. She had no recollection about any mention of possible consulting, but even if it had been mentioned, she would have expected the ethics office to be involved in that review. The official disputes that she confirmed that Dr. Sunderland was authorized to execute the agreement. Based on the phone call, the official expected to review the MTA and forward it to the NIMH Scientific Director for signature. The official's recollection was that all transfers of human tissue samples to researchers outside NIH were documented through MTAs. In early 1999 during an office move, the NIMH technology transfer office staff discovered a number of MTAs that had not been co-signed by the NIMH Scientific Director, as required by the written delegations of authority in effect at the time. One of these MTAs was the Sunderland-Pfizer MTA. When these MTAs were brought to his attention, the NIMH Scientific Director co-signed. He co-signed the Pfizer MTA on February 24, 1999. At that time, NIMH had already made three shipments of spinal fluid to Pfizer. (Exhibit 3, p.3) The co-signed MTA was retained in NIMH files. According to NIH, there was no evidence that Dr. Sunderland was given a copy of the 1998 MTA after Dr. Desimone signed, and Dr. Sunderland told NIMH he did not get a copy of the co-signed MTA until about several months ago when he requested it from the NIMH Executive Officer. Moreover, it is unknown when Dr. Sunderland learned about the existence of the co-signed MTA. The available evidence shows that Pfizer only had the MTA with Dr. Sunderland's signature. Under NIMH policy at the time, however, Dr. Sunderland was not the authorized signatory to execute the MTA. Questions arise about whether NIMH's transfer of samples was legally authorized and the legal implications for NIH. Furthermore, available evidence shows that NIMH management did not provide the co-signed versions to either Dr. Sunderland or Pfizer. This is of concern because NIMH management should have an interest in correcting an internal problem of unauthorized or improperly authorized material transfers. The problem cannot be corrected if management does not make NIH scientists aware of the error. In a conversation with Committee staff, the former NIMH technology transfer director acknowledged that this was an oversight. b. Plasma samples transferred without MTA. According to records from Pfizer and others, NIMH shipped 388 plasma samples to Pfizer on August 19, 2002. The Committee has no records of a material transfer agreement covering these plasma samples. The April 1998 MTA and the October 6, 2000, amendment to this MTA only covered coded clinical samples of spinal fluid and serum. c. Questionable amendment to MTA. The April 1998 MTA was executed using the Public Health Service Agreement MTA form and Dr. Sunderland was listed as the provider at his NIMH address. The October 6, 2000, amendment to the April 1998 MTA was executed on Pfizer letterhead and listed Dr. Sunderland at his home address. Committee staff asked NIH whether there were any amendments to the 1998 Pfizer MTA. NIH told the Committee staff that the NIMH Technology Transfer Office did not have an amendment but then NIMH asked Dr. Sunderland if there had been any amendments. At that point, Dr. Sunderland produced the October 2000 amendment. In an interview with Committee staff, the NIMH Technology Transfer Director stated that this amendment "would have raised eyebrows." Even though NIH told the Committee staff that Dr. Sunderland had the signatory authority to execute an MTA in 2000, because Dr. Sunderland had executed the MTA and had it co-signed by the NIH Scientific Director, the same process of authorization in effect in 1998 should have been used for the amendment in 2000. d. NIMH policy on MTAs lacked basic controls of accountability. According to an NIH e-mail to Committee staff, Dr. Sunderland had the authority to transfer the spinal fluid samples to Pfizer on his own without any approval or reporting, as long as Dr. Sunderland chose not to document the transfer without an MTA. Because he chose to execute an MTA, however, he did not have authority on his own to provide the samples. He needed clearance from the NIH Scientific Director. In other words, NIMH policy at the time, as represented by NIH, gave scientists more authority to provide government property to non-government researchers without any paperwork than if the scientists chose to do the paperwork. This kind of system raises the question whether such a policy incentivized a lack of accountability. Moreover, in 1999 the NIMH changed its written delegations of authority to permit Branch Chiefs, such as Dr. Sunderland, to have sign-off authority on MTAs. The stated rationale was to ensure that branch chiefs were aware of what materials were coming and going from the labs under their supervision. According to NIH in an e-mail to Committee staff, Dr. Sunderland had the authority after May 24, 1999 to approve his own transfers of material (including human tissue samples) outside NIH. This NIMH policy, or perhaps policy interpretation, raises the question about the lack of essential checks and balances to protect against fraud and error because the Branch Chief could approve his own MTAs for samples from studies in which he was involved as the Principal Investigator. e. Lack of clarity in NIMH policy on MTAs. Committee staff found an information bulletin, "NIH Technology Transfer and You," posted on the NIMH Technology Transfer Office (TTO) web site. The bulletin stated that that the NIMH version was revised on February 24, 2000. This bulletin stated in boldface type: Current NIH policy requires that MTAs be used whenever an NIH scientist sends out or receives materials, e.g., cDNAs, cell lines, antibodies, etc. These agreements must be signed by authorized IC personnel. The NIMH TTO Director at that time told Committee staff in an interview that MTAs were required. Other NIMH officials and NIH, however, disputed that the policy was so clear-cut. Rather, scientists were encouraged to use MTAs but not required to do so. In other words, MTAs were discretionary. NIMH officials interviewed by Committee staff also were not familiar with the TTO Bulletin. This area raises a question about the adequacy and accuracy of internal communication at NIMH. There is also a question about what was the actual policy. f. The MTA was a questionable mechanism for the transfer. Committee staff obtained records showing that Dr. Sunderland was the provider of spinal fluid samples in a 1989 Cooperative Research and Development Agreement (CRADA) between NIMH and Abbott Laboratories. Under this CRADA, Dr. Sunderland provided 115 samples of spinal fluid to Abbott. NIH and NIMH officials could not distinguish between the Abbott transfer and the Pfizer transfer in terms of why a CRADA was used with the transfer to Abbott but not with the one to Pfizer in 1998. Moreover, at a 1999 NIH Conference on Biomarkers, Dr. Sunderland stated: "In a large-scale collaboration between the NIMH, Pfizer, and OGS, we have embarked on a series of studies focused on one very important part of biomarker puzzle," and later stated that "cerebrospinal fluid markers are the focus of our collaborative efforts with Pfizer and OGS." (Emphasis added). Given such characterizations of the activity with Pfizer and OGS as well as other information, these officials believe that Dr. Sunderland and Pfizer were in fact engaged in a collaboration in which a CRADA would have been the appropriate mechanism to use. g. Reference to third-party collaborator in MTA should have triggered more scrutiny. Provision #2 in the April 1998 MTA stated that: "The Research Material will only be used for research purposes by Recipient and Recipient's collaborator in the UK, for the research projects described below, under suitable containment conditions." The mention of the Recipient's collaborator in the UK was a reference to Oxford Glycosciences, Ltd., (OGS), as part of the collaboration with Pfizer. OGS was part of the three-way collaboration with Pfizer and NIMH. OGS used 2D gel electrophoresis techniques to detect proteins in spinal fluid. OGS was not, however, specifically identified in the MTA. The involvement of a third-party collaborator raises a question of whether this was a modification of a routine material transfer and should have triggered further scrutiny from the Technology Transfer Office. The question is raised about whether uses and recipients of samples are adequately reported in the MTA and whether NIMH should have been made more aware of OGS and the use of the samples. Moreover, the MTA authorized the transfer of spinal fluid samples for the narrow purpose of the collaboration, which Pfizer refers to as the "unknown biomarker" projects. Records, however, produced to the Committee show that Dr. Sunderland provided over 2,100 samples to Pfizer for the "known biomarker" project. OGS, however, was not involved in this collaboration and it was actually a separate biomarker research project. A question is further raised whether the 2100 samples sent to Pfizer for this project were entirely unauthorized. h. Most of the samples transferred to Pfizer may not have been covered by the MTA and the MTA amendment. As mentioned before, the terms of the MTA related to transfers for the research purpose of the three-way collaboration of NIMH, Pfizer, and OGS. Pfizer calls this collaboration the "unknown biomarkers" project. The second project between Dr. Sunderland and Pfizer, did not involve OGS and Pfizer calls this "the known biomarker project." The NIH documents produced to the committee relating to the Pfizer collaboration state that the total number of samples sent to Pfizer equals 2132 vials for beta- amyloid 1-42, beta-amyloid 1-40, and tau. These are known biomarkers and relate to the "known biomarker" project. One of the NIH documents asserts that the samples sent to Pfizer were "through the NIH-approved MTA." The Committee, however, has not received any records of any MTA covering the known biomarker project. It is highly questionable whether NIH technology transfer and legal officials would find that the April 1998 MTA for the unknown biomarker project could be used to authorize transfer for the known biomarker project, even though it involved the same company and the same area of research, because the samples were used for a different research purpose. Science management concerns Three important concerns were raised: lack of retention of clinical research data, conflict of interest in committing NIH scientific resources, and NIH oversight of unpublished research. a. Lack of retention of clinical research data. When Dr. Molchan inquired about getting the leftover spinal fluid samples, she also asked about getting the data from her uncompleted lithium study. Dr. Sunderland informed Dr. Molchan that this data was no longer available: "Dear Sue, Over the last few days, we have been searching electronic files and paper files to see what we could find. Unfortunately, the data is no longer available. Just so you know, we had to go through several purges over the last few years when we moved offices, and anything over 5-7 years old was subject to purging. Since these studies and the resultant publications go back over 15 years in some cases, they were not carried forward to our limited space. . . . " (Trey Sunderland e-mail , March 14, 2005 to Susan Molchan). Dr. Molchan raised the issue of data retention in an e-mail to Committee staff: "Does NIH have a policy on what happens to data like this when scientists leave the NIH? It seems wasteful to repeat the same studies without having earlier results." Two senior NIH officials provided somewhat conflicting information. One official confirmed the policy of purging clinical data after seven years. Another official, however, had never heard of such a policy. The Subcommittee may wish to raise this question with NIH about what the policy is, and what the policy should be, on retention of clinical research, particularly in cases where the researcher has left NIH. b. Commitment of resources. Dr. Sunderland's collaborations with Pfizer resulted in the shipment of over 3,000 spinal fluid and plasma samples. These samples were extraordinarily valuable, both scientifically and commercially, because they contained useful information, they were linked to well-characterized clinical data (lots of medical details about the subjects), and the samples were taken from these same subjects over different points in time over several years. The Committee staff could find no evidence that showed in 1998 any NIMH official besides Dr. Sunderland who was even aware, much less supportive, of the merits of the Pfizer collaboration. Thus, Dr. Sunderland, while having concurrent financial interests with Pfizer, made the decision to commit 3,000 non-renewable taxpayer-supported human research samples. Techniques employed in proteomic analysis are new and evolving. Even if Dr. Sunderland may have been the scientist in the best position to evaluate whether the OGS technology was promising enough to consume these valuable human tissue samples, the intramural research program at NIMH or NIH may have had more than one expert in proteomics to assist in such a decision. Could Dr. Sunderland's scientific judgment have been better informed by consultations with other proteomic experts at NIH? The Pfizer projects may have been the most promising collaboration available in the search for biomarkers of Alzheimer's disease. Could an exploration of other private sector or academic partners produced a more promising result? Most importantly should a single scientist be the sole decisionmaker about the best use of these unique human tissue samples, especially with direct financial interests involved? c. NIH oversight of unpublished research. In the year 2000, Dr. Sunderland prepared a document called "Overview - GPB," in preparation for a review by the NIMH Board of Scientific Counselors. On page 3 of this document, the discussion about the Pfizer/OGS collaboration is as follows: "Perhaps the most interesting interaction is the three-way collaboration between the NIMH, Pfizer, Inc., and Oxford Glycosciences in England. This cooperative approach was first established in 1998 to investigate protein spots in the CSF of AD subjects and 'at risk' controls at baseline and over time. While this convergence of government investigators, the pharmaceutical industry, and a biotechnology firm has been highlighted by the NIH Director at a recent national biomarkers meeting as a way to leverage resources and scientific interest in the future, the proof of its power must come from the data, especially over time. Using high-throughput, exquisitely sensitive 2D gel electrophoresis techniques which provide quantitative data reflecting the up- and down-regulation of proteins in human CSF, we are generating cross-sectional data on over 1200 proteins in groups of AD and 'at risk' subjects. Perhaps most importantly, we will have longitudinal data in both these groups through repeat CSF collections that will allow us to track protein changes through the evolution of this illness." Under normal circumstances, the BSC would have been scheduled for another review of Dr. Sunderland's work in 2005. However, because in late 2004, NIMH officials believed that Dr. Sunderland was going to be leaving the NIH the BSC review was cancelled. The Committee staff has not found any publications related to the Pfizer/OGS collaboration. When asked by Committee staff to retrieve data or some kind of workproduct that resulted from this collaboration, NIH was unable to do so. In an interview with Committee staff, Karen Putnam indicated that all data related to the unknown biomarker project was maintained on- site at Pfizer. As Ms. Putnam noted in her December 7, 2004, letter to NIH: "Pfizer asked me to consult in the fields of statistics and data management. I was involved in specific projects exploring proteomics and statistical methodology. The Pfizer activities centered around discovery research, where the results were used to generate future hypotheses and directions of research. The results generated from my Pfizer outside activities were not part of the data involved in my current government job. All proteomics data were confidential and kept at the Pfizer site. The computer software and hardware used in exploring proteomics data was located at the Pfizer site." Outside counsel to Pfizer confirmed to Committee staff that this was essentially correct. Thus, the available evidence is that the unknown biomarkers project (or "discovery research" per Ms. Putnam) did not generate data that came into possession of the NIH. Under these particular circumstances, NIH was unable to report to the Committee what this collaboration had produced for NIH's scientific research program. Conclusion In sum, the records and interviews conducted in this investigation raise serious questions of misconduct in connection with, and inadequate oversight and control over, human tissue samples in NIH intramural programs. It should be noted that the Committee staff found no evidence that Pfizer had any knowledge relating to the questionable conduct of Dr. Sunderland in connection with the April 1998 MTA and the subsequent shipments of samples. Members of the Subcommittee may wish to pursue these questions at the hearing with witnesses and/or other appropriate action. <GRAPHICS NOT AVAILABLE IN TIFF FORMAT> MR. WHITFIELD. At this time, we have about 4 minutes left to cast two votes on the House floor, so Dr. Molchan, I will apologize to you, but we are going to take a recess here, go vote, and then we will be right back. We look forward to your testimony as soon as we return. So thank you. We will get your opening statement when we get back. [Recess] MR. WHITFIELD. I would like to reconvene this hearing, and we had indicated that we would have an opening statement from Ms. Baldwin when we resumed and she is not here, so at this time I would like to recognize Mr. Stearns of Florida for his opening statement. MR. STEARNS. Thank you, Mr. Chairman. I certainly want to thank you for holding this hearing and your leadership here in prodding everyone to do this, today and tomorrow, surrounding the NIH policies on tissue samples. I also want to thank Dr. Molchan for testifying today and for the courage for coming to the subcommittee when you were troubled about this concern. This hearing will ask if NIH has adequate policies in place to prevent diversion of human tissue samples for unauthorized purposes, and what is NIH policy on a chain of custody documenting human tissue samples from subject to each researcher that touches these samples, inside and out of NIH. Are we tracking the inventory or just willy-nilly sticking values on donations because this is what they are, a patient's literal blood, sweat, and tears, in the freezer with no tracking, no checks, and no balances. In other words, where is the oversight, where is the accountability here? This hearing raises the question about conflicts of interest at NIH, researchers involved in outside research assignments in industry. At the hearing in the summer of 2004, I was one who questioned Dr. Sunderland about a lucrative outside financial contract he had with Pfizer, and that now has surfaced again in this hearing. The extramural research that NIH funds and is supposed to oversee so carefully sends positive rippling effects across organizations, academia, and facilities across the United States. For example, Alzheimer's disease, neuro-imaging initiative, ADNI, for which the doctor as the program director relies on software-supported imaging equipment developed and manufactured by Siemens, Phillips, and General Electric. The three primary companies that develop and manufacture imaging are providing for the imaging aspects of the project, while the company that manufactures magnetic resonant imaging, the MRI coils that these giants of diagnostic imaging use, make them in Gainesville, Florida, in my congressional district. So many different people depend on the integrity of NIH human tissue policies, from patients hoping and praying for a cure for their disease to biotech companies to small engineering firms. Lastly, another question they have about this hearing is when the research subjects submitted a specimen CFS, did they consent to just a single study or did some at the NIH think it was a blanket consent for multiple uses and/or free reign over their spinal fluids for various research studies? In answer to that, I am troubled that it seems some at NIH did, in fact, handle these CFS specimens carelessly, sending them unauthorized to Pfizer without de- identifying them. Again, this committee has passed my data bill, H.R. 4127, which applies only to industry, but it sounds like we need to consider Federal agencies handling of Social Security and other sensitive personal data as well. Mr. Chairman, I thank you for exploring these issues and I yield back. [The prepared statement of Hon. Cliff Stearns follows:] PREPARED STATEMENT OF THE HON. CLIFF STEARNS, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF FLORIDA I want to thank Chairman Whitfield for holding this hearing today and tomorrow surrounding NIH policies on tissue samples. And Dr. Molchan, thank you for testifying today, and for your courage in coming to this Subcommittee when you were troubled. This hearing will ask if NIH has adequate policies in place to prevent diversion of human tissue samples for unauthorized purposes? And, what is NIH's policy on a chain of custody, documenting human tissue samples from subject to each researcher that touches it, inside and outside of the NIH? Are we tracking the inventory, or just willy-nilly, sticking valued donations, because that is what they are, of patient's literal blood, sweat and tears, in the freezer with no tracking, no checks and balances? Where is the oversight, the accountability? Also, this hearing raises questions about conflicts of interest of NIH researchers involved in outside research assignments in industry. At the hearing in the summer of 2004, I was one who questioned Dr. Sunderland about a lucrative outside financial contract he had with Pfizer, that now surfaces again in this hearing. The extramural research that NIH funds, and is supposed to oversee so carefully, sends positive rippling effects across organizations, academia, and facilities across the nation. For example, the Alzheimer's Disease Neuroimaging Initiative (ADNI), for which Dr. Molchan is the program director, relies on software support and imaging equipment developed and manufactured by Siemens, Philips, and General Electric, the three primary companies that develop and manufacture imaging equipment. Well, the company that manufactures the magnetic resonance imaging (MRI) coils that these giants of diagnostic imaging use makes them in Gainesville, Florida: INVIVO Corporation. So, many different people depend upon the integrity of NIH's human tissue policies, from patients hoping, praying for a cure for their disease, to biotech companies, to small engineering firms. Another question I have about this hearing is when the research subjects submitted a specimen of cerebrospinal fluid (CSF), did they consent to just a single study, Dr. Mochan's? Or did some at the NIH think that it was a blanket consent for multiple uses and/or free reign over their spinal fluid for various research studies? And, advancing from that, I am troubled that it seems some at the NIH did in fact handle these CSF specimens carelessly, sending them, unauthorized, to Pfizer without de-identifying them! Again, this committee has passed my DATA bill, HR 4127, which applies only to industry, but it sounds like we need to consider federal agencies handling of Social Security numbers and other sensitive, personal data as well. Thank you for exploring these issues. MR. WHITFIELD. Thank you, Mr. Stearns. At this time I recognize Ms. Baldwin from Wisconsin. MS. BALDWIN. Thank you, Mr. Chairman. The NIH is one of our national treasures. The intramural research done at NIH and the extramural research done in cooperation with outside partners is truly amazing and sometimes awe-inspiring. So much of today's most promising research involves human tissues. In order to translate biomedical discoveries into real improvements for people's medical care, we must first use human tissues to test a treatment or develop a new theory about how a disease develops. The work that is done with these human tissues holds the potential to do so much to advance human health. I am distressed to hear about apparent lapses in accountability with regard to human tissue samples collected at the NIH. Why doesn't the NIH have a centralized system for tracking its tissue samples? Why is there no institute-wide inventory or accounting of what happens to these samples when a study ends? As our full committee and the Subcommittee on Health engage in discussions about health information technology, it seems like NIH could be a leader in this regard but at least in this arena, it certainly is not. I think that what is most shocking to me is the carelessness and the way in which some at NIH appear to be treating such a precious commodity. While it is true that the samples are in freezers across the NIH and they might be vials of fluid or dishes of cells, it is important for us to remember that each of these samples originated in a person, and that person chose to share, chose to make a gift so that research could advance. At the very least, we must have practices in place that guarantee donor privacy and we need to ensure that donors are giving informed consent about how their donation will be used. Lastly, a lot of these human tissues are non-renewable, and as I said earlier, they are a precious resource. We need to make sure that they are being used in the most appropriate and ethical way, not simply handed off to private companies. Again, I am really shocked that some at the NIH would treat human tissues so carelessly, and that individual researchers would be given almost complete control over tissue samples without having to report to an impartial IRB, Institutional Review Board, like researchers at every academic research institution have to do. I look forward to today's discussion, and I hope this hearing will lead us towards some answers. I want to extend a special thank you to today's witness, Dr. Molchan. I commend you for bringing information forward to this committee's attention. Thank you, Mr. Chairman. I yield back. MR. WHITFIELD. Thank you. At this time, I will recognize the full committee Chairman, Mr. Barton of Texas. CHAIRMAN BARTON. Thank you, Mr. Chairman, for holding this hearing. As I said at the last set of oversight hearings on NIH, the hallmark of this committee has always been its oversight responsibility and its willingness and ability to hold agencies responsible under its jurisdiction that produces results and better government and better services for the American people. When we held oversight hearings about the NIH ethics system several years ago, we found that there were weaknesses in the system at that time, and that those weaknesses were more severe than we had previously recognized. To his credit, Dr. Zerhouni, who had a ringside seat at those hearings, took the facts of the hearing seriously and changed and reformed the NIH ethics system. Today, we are going to take a look at how the NIH protects its most precious assets, that is, the material that is at the core of NIH research mission, human tissue samples. Once again, after extensive investigation, on a bipartisan basis, I might add, we have found deeper concerns regarding human tissue samples at NIH than we first believed. We have found a lack of a centralized database, lack of oversight. This lack of a centralized database and lack of oversight could, and probably does, leave NIH laboratories vulnerable to the risks of theft and abuse. We know from previous investigations that the NIH has an inventory system, but NIH tells us that it has no centralized inventory system that could tell the NIH director how many vials of tissues are in freezers at a particular institute. It would really be a shame if we find out that the National Institutes of Health has more control over its paperclips and trashcans than it has over its human tissue samples. The committee has investigated a case and found evidence of a serious breach of trust. This case is focused on Dr. Trey Sunderland, who is supposed to be a witness later today in these hearings. He is a very noted, and I might add, respected researcher in the field of Alzheimer's disease. I wish we were holding a hearing to congratulate him on some great discovery that he has made to cure or at least alleviate the hazards of Alzheimer's. Instead, we are going to have to discuss a way of how he used his position to use NIH spinal fluid samples to further his own undisclosed personal consulting. The information provided so far to the committee shows that a private corporation, Pfizer Corporation, paid Dr. Sunderland $285,000 during the 1998-2003 time period to consult on two projects involving spinal fluid samples that Dr. Sunderland had sent to Pfizer. During the same time period, Pfizer also paid Dr. Sunderland approximately $300,000 for lectures. These figures don't count an additional $200,000 for undisclosed activities with other companies. There is evidence that he advised his subordinate to conceal these consulting activities involving the samples. This is from an official who chaired for 10 years the committee that reviews the ethics of conducting mental health research on human beings. This certainly appears to be a betrayal of the public trust that NIH so much stands for. These hearings underscore the need to enact NIH reauthorization and reform legislation. The NIH director must have some baseline of information about NIH assets if we are going to gain new efficiencies and hopefully more effective ways to translate research into better healthcare. NIH reauthorization legislation is of the highest importance. Out of this investigation, deserving questions and concerns, we can use these hearings to make NIH stronger and better. The National Institutes of Health is, indeed, a national treasure. It must be cherished, protected, nourished, and allowed to flourish. Today's hearing is a first step towards strengthening the public trust in NIH and preserving confidence in its integrity. I want to thank you, Mr. Chairman, and also the subcommittee Ranking Member, Mr. Stupak, for the bipartisanship nature of this investigation. I would also like to thank the Ranking Member of the full committee, Mr. Dingell of Michigan, for his support. Finally, I want to say that I look forward to working with Dr. Zerhouni and others to improve in this area and to help NIH become better managed, and thus be able to deliver the results for the health of America that we so depend on NIH to do. With that, Mr. Chairman, I yield back. [The prepared statement of Hon. Joe Barton follows:] PREPARED STATEMENT OF THE HON. JOE BARTON, CHAIRMAN, COMMITTEE ON ENERGY AND COMMERCE Mr. Chairman, I am glad you are holding these hearings. As I said at the last set of NIH oversight hearings, I hope one of the hallmarks of my chairmanship of the Energy and Commerce Committee will be holding agencies responsible and produce better government and better services and policies for the American people. Two years ago, when we held oversight hearings about the NIH ethics concerns, we discovered that the weaknesses in the NIH system were severe. Dr. Zerhouni, the Director of NIH, had a ringside seat and realized that NIH's reputation was on the line. In light of our hearings, the NIH ethics system has been overhauled and reformed. Today we look at how NIH protects precious assets, the human tissue samples that are at the core of the agency's research mission. Once again, after extensive investigation, we have found deeper concerns regarding human tissue samples at NIH than first believed. Incredibly, we have found a lack of a centralized database and oversight at NIH that leaves NIH labs vulnerable to theft and abuse. We know from previous investigations that NIH has an inventory system for its property, but NIH tells us it has no centralized inventory system that could tell the NIH Director how many vials of tissue are in freezers at a particular institute. It appears that the agency can account for its paper clips better than its invaluable research material. The Committee's investigation has focused on one particularly brazen breach of trust. Dr. Trey Sunderland, a noted and respected researcher in the field of Alzheimer's disease, has discovered something that may have been even more important to him. He has discovered how to make money by using NIH's collection of spinal fluid samples in an undisclosed, personal consulting arrangement with a drug company. The information provided to the Committee is that Pfizer paid Dr. Sunderland $285,000 during the 1998-2003 time period to consult on two projects involving spinal fluid samples Dr. Sunderland sent to Pfizer. During this same time period, Pfizer also paid Dr. Sunderland around $300,000 for lectures. He also earned almost $200,000 more for undisclosed activities with other companies. Dr. Sunderland might have been proud of his work, but he wasn't. There is evidence that he advised his subordinate to conceal consulting activities involving the samples. All this from an official who for 10 years chaired a committee that reviews the ethics of conducting mental health research on human beings. Mr. Chairman, this amounts to a breathtaking betrayal of the public trust and of NIH values. These hearings underscore the need to enact NIH reauthorization legislation. The NIH Director must have some baseline of information about NIH assets. If we are going to gain new efficiencies and hopefully more effective ways to translate research into better healthcare, enacting NIH reauthorization legislation is of great importance. Out of this investigation of disturbing questions and concerns, we can use these hearings to make NIH stronger. NIH is indeed a national treasure. It must be cherished. Today's hearings are a first step toward strengthening public trust in NIH research and preserving confidence in NIH's integrity. I thank you and Mr. Stupak for the bipartisan investigation. I also thank Mr. Dingell for his support of this investigation. Finally, I look forward to working with Dr. Zerhouni and the leadership of NIH on this matter and helping NIH become better managed and better able to improve the health of the American people. MR. WHITFIELD. Thank you, Chairman Barton. At this time I recognize Mr. Walden of Oregon for his opening statement. MR. WALDEN. Mr. Chairman, I am going to waive an opening statement this afternoon. Thank you. MR. WHITFIELD. Thank you. Mrs. Blackburn of Tennessee. MRS. BLACKBURN. Mr. Chairman, I will waive and reserve my time for questions. [Additional statement submitted for the record follows:] PREPARED STATEMENT OF THE HON. DIANA DEGETTE, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF COLORADO Mr. Chairman, thank you for holding this important hearing. The issue is not just about the alleged wrongdoing of one research scientist at the National Institutes of Health (NIH). The larger issue we face is the systemic breakdown in how we protect patients who courageously agree to participate in clinical research. The NIH is the premiere biomedical research entity in the world. As a result, it is imperative that the research protocols used by the NIH be of the highest integrity. Clearly, that is currently not the case. Let me first recognize our witness today, Dr. Susan Molchan, who brought this issue to the attention of the subcommittee. I believe we all owe you a debt of gratitude for coming forward. Tomorrow we will hear from a number of witnesses from the NIH. The subcommittee's staff report raises many issues that our NIH witnesses must answer and I look forward to questioning the agency tomorrow about a number of my concerns. Specifically, I am concerned that it appears as though the NIH cannot account properly for human tissue samples in its possession or for the data generated by the use of those samples in biomedical studies. I would posit that the oversight function at NIH is in need of serious repair. Its investigatory ability is clearly inadequate when this Subcommittee has to uncover what the NIH cannot, even when it is trying. I sincerely hope that these hearings will assist the agency in straightening up the mess caused by its administrative shortcomings, just as our last hearings helped the NIH shore up its ethical standards. When he was shown the extent of the ethical loopholes at his agency, NIH Director Dr. Zerhouni was very responsive. I have no doubt that he will be equally responsive in addressing the travesty created by the lack of accountability that this inquiry has uncovered. All that said, what is most worrisome to me is the abuse of patients' trust. These people, victims of Alzheimer's Disease or their relatives, as well as some courageous individuals who have participated in the control groups, have submitted periodically for a decade or more to time consuming and painful spinal taps. They believed that the decisions regarding the use of these samples were made by the best scientific judgment in the country. It is possible that only such an esteemed institution as the NIH could have enlisted these volunteers and convinced them to return again and again to give spinal fluid. Yet, we now know that some of these committed patients were never told that the experiments that used their samples had been aborted. Others were never given the results of completed efforts. Nobody was informed that samples left over from certain experiments were shipped from the NIH to private drug companies. Patients were not informed that there was a chance that their names, names that were supposed to be divorced from the samples in the event of them being used for research, could be inadvertently revealed. This did in fact occur when one of the Sunderland shipments to Pfizer revealed patient names to company researchers. Mr. Chairman, these practices are unacceptable. Human subjects and their donated tissues simply must be protected as a first order of business by government researchers. The officials at NIH must be able to give ironclad assurances to these volunteers. To solicit cooperation and to take human tissue without proper protections in place is simply wrong, whether it is at the NIH or anywhere else. Last week, I introduced H.R. 5578, the "Protection for Participants in Research Act of 2006" to provide clear and consistent protections for human subjects who take part in clinical trials, as well as providing clear guidelines to those conducting medical research. Specifically, this measure strengthens patients' rights to informed consent before subjecting to human subjects research. Perhaps this bill, given what we hear today and tomorrow from our panelists, could be used as a basis for further protecting human subjects, whether it is at the NIH, in universities, or at private companies. I yield back the balance of my time. MR. WHITFIELD. Thank you. That concludes our opening statements, and at this time, Dr. Molchan, we will call you as our first and only witness of the day. Dr. Susan Molchan is the Program Director of the AD NeuroImaging Initiative, Neuroscience and Neuropsychology of the Aging program at the National Institute on Aging. Dr. Molchan, as you may or may not know, in the Oversight and Investigations Subcommittee, we do have, as a matter of policy, to take testimony under oath. I would ask you, do you have any objection to testifying under oath today? DR. MOLCHAN. No, I don't. That is fine. MR. WHITFIELD. Okay. Under the rules of the House and also the rules of the committee, you are entitled to be advised by legal counsel. Do you have legal counsel with you today? DR. MOLCHAN. No, I don't. MR. WHITFIELD. You are on your own? DR. MOLCHAN. Yeah. MR. WHITFIELD. If you would stand, I would like to swear you in. [Witness sworn] MR. WHITFIELD. Thank you. You are now under oath, Dr. Molchan, and at this time I recognize you for 5 minutes for your opening statement. STATEMENT OF SUSAN MOLCHAN, M.D., PROGRAM DIRECTOR, AD NEUROIMAGING INITIATIVE, NEUROSCIENCE AND NEUROPSYCHOLOGY OF AGING PROGRAM, NATIONAL INSTITUTE ON AGING, NATIONAL INSTITUES OF HEALTH, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES DR. MOLCHAN. Thank you, Mr. Chairman. Mr. Chairman and members of the committee, my name is Dr. Susan Molchan from the National Institute on Aging at the NIH where I have worked since 2001 as the Program Director for clinical studies and Alzheimer's disease. I serve as a medical officer in the Commissioned Corps of the United States Public Health Service. Thank you for this opportunity to participate today. I have been asked to address my experience with human tissue samples at the National Institute of Mental Health where I worked for 9 years. I will address my experience specifically with one type of especially precious sample, spinal fluid, that I collected from a number of patients with Alzheimer's disease and volunteers in the early '90s. As a young scientist at the NIMH, National Institute of Mental Health, I conceived and conducted a study that now has implications for Alzheimer's research. In the process of my research, I obtained a very valuable material, spinal fluid. These samples can be obtained only with the consent and understanding of each and every patient. As a doctor, my first obligation is to advocate for patients who put their trust in me. Some of these patients had contributed their time and bodies to a number of my research studies and others at the NIMH. These good people are always ready to help and work on Alzheimer's in any way my colleagues and I asked. While at NIMH, a redirection of the program occurred. New goals made it impossible for me to continue my work. Lack of support was intense and I was not encouraged to stay, so I went to work at the FDA for a few years until 2001, when I was recruited to my current position as a program officer at the National Institute on Aging where I work with Alzheimer's scientists throughout the country. In 2004, some of these scientists, university scientists who are leaders of the National Institute of Aging's clinical trials consortium where I work now, which serves as the primary mechanism through which NIH funds studies on the treatment of Alzheimer's disease, proposed a study very similar to the one I had done while at the National Institute of Mental Health. Several of my very esteemed colleagues pressed me to obtain the samples I had collected. Such samples can be stored in freezers for years, and my colleagues and I had every reason to believe that they would still be available. The head of the branch where I worked at NIMH located and sent a small subset of the spinal fluid samples to a university colleague for analysis. Twenty-five people had participated in the study, although I couldn't recall on how many I had collected spinal fluid for sure. Some got one spinal tap, others had gotten two. I did know I had collected it on more than the eight Alzheimer's patients and two volunteers on whose fluid was located. The individual responsible for the samples at the NIMH, Dr. Sunderland, e-mailed me that some of the samples had been lost in freezer thaw problems. A request to inspect the freezers to hopefully help find some samples was denied. By the end of January 2005, intriguing data resulted from analyses of the spinal fluid samples that we were able to recover. Incomplete as it was, it contributed to the success of a grant proposal that shows promise in advancing knowledge on the mechanisms and treatment of Alzheimer's disease. Several colleagues agreed that the data from these samples were worth publishing in a scientific journal. These senior Alzheimer's researchers again pressed me for an answer as to why only a small amount of fluid was available, and only on a subset of the participants. This would need to be explained in any scientific submission of the data. Since Congress had shown an interest in this matter, some progress has been made. I thank you for your interest in human tissue specimens that are so important to public health research. Thank you. [The prepared statement of Susan Molchan follows:] PREPARED STATEMENT OF SUSAN MOLCHAN, M.D., PROGRAM DIRECTOR, AD NEUROIMAGING INITIATIVE, NEUROSCIENCE AND NEUROPSYCHOLOGY OF AGING PROGRAM, NATIONAL INSTITUTE ON AGING, NATIONAL INSTITUTES OF HEALTH, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Chairman and Members of the Committee: My name is Dr. Susan Molchan, from the National Institute on Aging (NIA) at the National Institutes of Health (NIH), where I have worked since 2001 as a program director for clinical studies on Alzheimer's disease. I serve as a medical officer in the U.S. Public Health Service. Thank you for this opportunity to participate today. I have been asked to address my experience with human tissue samples at the National Institute of Mental Health (NIMH), where I worked for nine years. I will address my experience specifically with one type of especially precious sample-spinal fluid- that I collected from a number of patients with Alzheimer's disease (AD) and volunteers in the early 1990s. As a young scientist at NIMH, I conceived and conducted a study that now has implications for AD research. In the process of my research, I obtained very valuable material-spinal fluid. These human samples can be obtained only with the consent and understanding of each and every patient. Those who participate in our research trust that their fluid specimens will be handled carefully. As scientists, we carefully document and store this material. As a doctor, my very first obligation is to advocate for the well-being and intentions of the patients who put their trust in me. Some of these patients had contributed their time and bodies to a number of my research studies and others at the NIMH. These good people were always ready to help in work on AD in any way my colleagues and I asked. While at NIMH, a redirection of the program occurred and the new goals made it impossible for me to continue my work. Lack of support was intense for this project and I was not encouraged to stay. I went to work at the FDA for a few years, until 2001, when I was recruited to my current position as a program officer at NIA, where I work with AD scientists throughout the country. In 2004, the university scientists who are the leaders of the NIA's clinical trials consortium, which serves as the primary mechanism through which NIH funds studies on the treatment of AD, proposed a study very similar to the one I had done at the NIMH. Several of my esteemed colleagues pressed me to obtain the samples I had collected. Such samples can be stored in freezers for years, and my colleagues and I had every reason to believe that they would still be available. As research on AD has progressed, the need for spinal fluid samples has increased, as they may shed light on treatment options for this increasingly prevalent and devastating disease. All available scientific resources are needed to fight AD. The head of the branch where I had worked at NIMH located and sent a small sub-set (one cc per individual participant of the approximately 50 cc that I'd collected from each) of the spinal fluid samples to a university colleague for analyses (tests that were covered on the consent form under which study participants allowed me to collect their samples). Twenty-five people had participated in the study as documented on a Continuing Review memo to the NIMH IRB, dated July 1, 1993. Although I hadn't collected spinal fluid on all of them, I had collected it on more than the 8 AD patients and two volunteers on whom fluid was located. The individual responsible for the samples at the NIMH emailed me that some of the samples had been lost in "freezer thaw problems." A request to inspect the freezers to hopefully find some samples was denied. By the end of January, 2005 intriguing data resulted from analyses of the spinal fluid samples that we were able to recover. Incomplete as it was, it contributed to the success of a grant proposal that shows promise in advancing knowledge on the mechanisms and treatment of AD. Several colleagues agreed the data from these samples were worth publishing in a scientific journal. These senior AD researchers pressed me for an answer as to why only a small amount of fluid was available, and on only a subset of the participants. This would need to be explained in any scientific submission of the data. Since Congress has shown an interest in this matter, some progress has been made. I thank you for your interest in human tissue specimens that are so important to public health research. MR. WHITFIELD. Dr. Molchan, thank you very much for cooperating with the committee and your willingness to come and testify. How long were you actually at the National Institute of Mental Health? DR. MOLCHAN. I worked at the National Institute of Mental Health for 9 years, from 1987 to 1996. MR. WHITFIELD. Eighty-seven to '96, and was Dr. Sunderland there during that entire period? DR. MOLCHAN. Yes, he was always my supervisor, yes. MR. WHITFIELD. Okay, before I get to the lithium study, just to clarify here, when we talk about human tissue, and when we look at the specific testing that you were involved in, we are talking about spinal fluid? DR. MOLCHAN. Yes. MR. WHITFIELD. But when we talk about human tissue in general, we are talking about things like subcellular DNA, we are talking about tissues like skin. DR. MOLCHAN. Anything that comes from body parts. Blood is a tissue, for example, spinal fluid is a tissue, as are the more solid-- MR. WHITFIELD. Okay. DR. MOLCHAN. --components like skin. MR. WHITFIELD. And fetal tissue, all of those things? DR. MOLCHAN. Yes. MR. WHITFIELD. Okay. Now, the lithium study that you were involved in, were you responsible for obtaining the spinal fluid for that study? DR. MOLCHAN. I was responsible for obtaining most of the samples. The study was initiated by me and if it was going to get done, I was the one who had to do it. So I obtained most of the samples, though when I had to be somewhere else colleagues would step in and do so. MR. WHITFIELD. And you said that the samples came from some Alzheimer's patients, as well as two patients who had no medical problems? DR. MOLCHAN. The subset of the samples that were located last year, right. There were several Alzheimer's patients, eight Alzheimer's patients and two of the normal volunteers that had done the study. MR. WHITFIELD. So when you are dealing with an Alzheimer's patient, how do you obtain their consent for a spinal tap? DR. MOLCHAN. We did have procedures, clear procedures in place for that and they would co-sign, have a spouse or someone else responsible co-sign and understand. MR. WHITFIELD. And what was the total volume of spinal fluid that you were able to collect? DR. MOLCHAN. Generally we collected approximately 25 cc's or 25 milliliters, which is about five teaspoons. MR. WHITFIELD. And that is from each person? DR. MOLCHAN. That is from each person during one spinal tap, yes. MR. WHITFIELD. And you had a total of nine or so patients that you obtained 25 cc's from? DR. MOLCHAN. There were more than that, and what was important about this study that I had done is we were able to get two spinal taps on people, one while they were taking medication and the other when not on the medication so we could compare. MR. WHITFIELD. Okay. So anyway, you used a small amount of this fluid for your research, and then you left the National Institute of Mental Health and went to FDA? DR. MOLCHAN. Yes. MR. WHITFIELD. And then when you went over to the National Institute of Aging, a similar study came up and so you thought well, it will be great to go back and get to this spinal fluid? DR. MOLCHAN. Yes. MR. WHITFIELD. And so you went to see Dr. Sunderland about the availability, I am assuming, or you talked to him or you made inquiry? DR. MOLCHAN. Well, I inquired through one of my former NIMH collaborators originally who was still at the NIMH to inquire for me. I followed up later with Dr. Sunderland by e-mail, I believe. MR. WHITFIELD. Because he was the person-- DR. MOLCHAN. Responsible-- MR. WHITFIELD. --responsible-- DR. MOLCHAN. --for them. Since he was the chief of the program there, the chief of the lab, yes. MR. WHITFIELD. And so were you able to obtain samples from him? DR. MOLCHAN. He did send samples from eight of the patients, eight of the Alzheimer's patients, two of the normals, but only half a cc from each spinal tap, half a cc out of 25 cc's. Now, I understand we didn't need a whole lot, but we would have liked a little more than a half of a cc, but when we asked for a little bit more or what happened to the rest of it, we just never got any good documentation of that. MR. WHITFIELD. Okay. So you never did find out how much they had? Did they give you any explanation of where it was or anything? DR. MOLCHAN. Just that some of it had been lost in freezer failures, freezer thaws, and that it has been a long time. So no, nothing solid, nothing that made sense, because I knew the recordkeeping where this was done was very careful. The spinal fluid is very important stuff for our research and Dr. Sunderland was always very careful about documenting how much we had and the research assistants would know in what freezers and what part of the--you know, whether it was collected late or early in the spinal tap. It is very detailed information. MR. WHITFIELD. So as you sit here today, do you know for a fact what happened to it? DR. MOLCHAN. No. MR. WHITFIELD. You still do not know, okay. DR. MOLCHAN. No. MR. WHITFIELD. Okay. Now, you were at two institutes at NIH, and was there a protocol, a policy on the collecting, the storing, the tracing, the using of human tissue samples? DR. MOLCHAN. Well, where I am now in the extramural program which deals with the university researchers, you know, helping to administrate and plan Alzheimer's research among the university community, whereas the intramural program does actual hands-on research, which I was in when I was in the National Institute of Mental Health. At that point, yeah, I just don't know. I wouldn't know about it. I think you are talking about the intramural program specifically, and I didn't know when I was there. MR. WHITFIELD. But you obviously were surprised that you were not able to obtain any information about the availability of spinal fluid? DR. MOLCHAN. Yes. MR. WHITFIELD. And that you were not able to get the volume that you really needed to-- DR. MOLCHAN. Yes. MR. WHITFIELD. --for your purposes? DR. MOLCHAN. Yes, and I couldn't understand that. MR. WHITFIELD. Now, did the people that you reported to at the National Institute of Aging, did you tell them about it and did they go to Dr. Sunderland about this issue, or was it just dropped? DR. MOLCHAN. I tried to keep it within the National Institute of Mental Health, so I did mention it to my colleagues at Aging, but again, this was a separate time and place when I was at the NIMH. It is an intramural program working specifically with Dr. Sunderland, so while I let them know about it, I didn't expect or ask them to do anything. I told them I was following up with Dr. Insel and some other people. MR. WHITFIELD. Now, at the time that you were at the Mental Health Institute, were you aware of scientists who had outside consulting agreements with-- DR. MOLCHAN. Yeah. MR. WHITFIELD. So that was not anything unusual about having these consulting agreements? DR. MOLCHAN. I don't have enough information to know how common or usual it was, but I know people did it and that there were ways to go about doing it. MR. WHITFIELD. But you are not familiar with the disclosure requirements or anything like that, is that correct? DR. MOLCHAN. For me with the intramural program at NIMH, these procedures have been evolving, these relationships between academia and industry, which I reiterate can be very positive if done in the right way. So I wasn't involved in any myself, I was busy enough with my work at the NIH so I never looked into the rules of it seriously. MR. WHITFIELD. Well, from the knowledge and experience that you have had working there and your professional occupation as a physician and scientist, would you agree with the statement that the protocol in place for tracking and collecting and using human tissues leaves something to be desired at NIH or do you have enough information? DR. MOLCHAN. Well, just from my experience, it apparently did. I mean, I hope this is an unusual--I think it is an unusual situation and otherwise, it is outside of my sphere of experience as to what an overall policy is there. I would have to confer with other people. MR. WHITFIELD. Now, tell me, who is Karen Putnam? DR. MOLCHAN. Karen Putnam, she worked with Dr. Sunderland for many years as a research assistant. She was, I believe--I don't know if she was a master's degree level. She helped with everything from doing neuropsychological testing on people to inputting data to helping organize data, just kind of keeping track of things in general. So she was a research assistant. MR. WHITFIELD. And did you work with her on trying to obtain these samples? DR. MOLCHAN. No. Karen, as far as I knew, had left the NIMH a few years ago, though she may have still been doing some consulting. I don't know. I really wasn't in touch with them. MR. WHITFIELD. Okay. My time is expired. Mr. Stupak? MR. STUPAK. Thank you, Mr. Chairman. Doctor, thanks for appearing today. You said Dr. Sunderland was your supervisor? DR. MOLCHAN. Yes. MR. STUPAK. When you drew these samples, these cerebral spinal fluid, did he supervise that withdrawing of these samples? DR. MOLCHAN. No. MR. STUPAK. Okay. You indicated in a statement to the Chairman that sometimes your colleagues would step in and draw some of these samples for you, correct? DR. MOLCHAN. Yes. MR. STUPAK. Okay. Is there any way that Dr. Sunderland or someone else then could say that they sort of had ownership of these samples because they drew them? DR. MOLCHAN. I have never heard of such a thing. From what I understood when I left and otherwise, the samples belonged to the Government. I don't think anybody would. MR. STUPAK. So in this informed consent from these donors, did it identify the owner of the sample then being the NIH or NIMH? DR. MOLCHAN. I would have to look at the language specifically, but again, that is such a broad question that we don't usually get into the details of. I guess most of us just assume that it belongs to the NIH, the government. MR. STUPAK. You said you left NIMH and when you left, was your study supposed to continue or did it stop or what happened there? DR. MOLCHAN. I assumed it would continue. When other doctors left, especially with clinical studies where patients had been involved, the studies were continued, the data analyzed and then written up and published. MR. STUPAK. Sure. DR. MOLCHAN. So I assumed that the people who were following on where my position was would continue it, but apparently that didn't happen. MR. STUPAK. Do you know why your study stopped? DR. MOLCHAN. I don't, no. MR. STUPAK. Okay. DR. MOLCHAN. Why it wasn't followed up, no. MR. STUPAK. And you can't recite for us what the proper protocol or policy was on releasing any of these samples at NIMH then, the samples you drew? Is there a certain procedure you have to follow before you release the samples? Say you release it to Pfizer-- DR. MOLCHAN. The only samples I used were with a scientific collaborator within the NIH and to look at the samples as stipulated in the consent form to look at the effects of this drug, on and off the drug, so that was the only experience I had. It was all within the NIH. Other than that, I drew the samples and put them in the freezer and the research assistants would catalog them. MR. STUPAK. And before you would release it to collaborative effort to work with somebody else, whether academia or whatever it is, you would know how much of the sample was sent, how much was requested-- DR. MOLCHAN. Yes. MR. STUPAK. --and the manner or method in which it was going to be used? DR. MOLCHAN. Very much so. It was very specific. Depending on what you measure, you need certain amounts. I mean, sometimes you just need a tiny--you know, a drop, other times you might need as much as a few cc's, half a teaspoon. MR. STUPAK. Okay. When you were at NIH or the National Institute of Mental Health and you went over to the Institute on Aging, was it necessary or were you required to get any new consent forms from any of the donors as these samples were now being used in a different part of the agency than which was originally drawn for? DR. MOLCHAN. Well, again, the samples were collected in an intramural program. I am in the extramural program. I don't know if--I knew what we were interested in was covered in the consent form, because we wanted to look at the effects of the drug on the paired samples. And other than that we did academic circles, which in the past have been commonly done. People would make an agreement and I will send you so much and do such and such on it, and then send you the information, send you the data. MR. STUPAK. If you can answer this one, if Dr. Sunderland teamed up with Pfizer to do some research outside of NIH for Pfizer's benefit, when a sample is given from a donor, it is for research purposes, so could the research being done by Pfizer meet the definition in that consent agreement, or is the focus of the consent agreement from the donor that the ownership control use is for the government and not for outside? DR. MOLCHAN. Well, there are mechanisms to have a pharmaceutical company or a biotech company do an assay for you, and in exchange for doing the assay--I mean, some of these are very expensive to do, so it actually can be very helpful. MR. STUPAK. So the issue here really is not how the sample might have been used, whether internally or externally, but the lack of knowledge or-- DR. MOLCHAN. Well, their samples--the way they are collected, the reason was to look at the effects of this drug on some of the proteins, some of the things we could measure in the spinal fluid. It is very specific to the actions of this drug, which has become of more interest recently in Alzheimer's research. So that was very specific. MR. STUPAK. But was that for all of your samples you drew was for a very specific purpose type of research? DR. MOLCHAN. Well, for each protocol that we did at the time, we collected, as you have gathered, a lot of spinal fluid, and for each protocol we had, as I recall, a separate consent form. MR. STUPAK. Okay. I guess that is the best way to get a consent form is--okay. So it would have been unusual then to have it go outside of NIH in the protocol that you had established to get this donation, if you will? DR. MOLCHAN. In a general sense or from my study? I mean-- MR. STUPAK. The private gain companies in the mind of the donor, if you will. What is their expectation of how the sample is going to be used I guess is what I am trying to get at. DR. MOLCHAN. Right. I would have to look at the exact wording on the consent form, but for the samples I drew, at least, they needed to be looked at in a paired way, on and off drug, to try to look at the effects of the drug. MR. STUPAK. Sure, because you had a specific purpose that you were trying to test. DR. MOLCHAN. Yes, and I recall that all protocol had a specific purpose. Again, the consent forms have been evolving and IRB policies, and from what I recall, we needed to get a specific consent form for each protocol that we did, because a number of the protocols did involve drawing spinal fluid. MR. STUPAK. Sure, but if I am a donor, how many cc's would you take? DR. MOLCHAN. About 25. MR. STUPAK. Okay, 25. And I give permission and I give 25 cc's, and you used 5 cc's, would that consent then restrict the remaining 20 cc's from going elsewhere, or was it only for your study? DR. MOLCHAN. As long as it was sent with the understanding of what was in the consent form and set up through NIH-approved mechanisms, that I think would be reasonable. MR. STUPAK. Okay. I guess we will have to take a look at one of those consent forms. If you have more than what you are using, I guess another thing I am trying to arrive at, though, the remainder then is it restricted within NIH or can it be used outside of NIH? DR. MOLCHAN. Oh, no. In these things, we keep them in these big freezers which are very carefully regulated and backed up and controlled. We keep some of what we collect, whether it is blood or spinal fluid, in hopes that an interesting assay--something interesting we will want to measure in the future will come along. So these things literally can be stored sometimes for decades. MR. STUPAK. Okay. In fact, in your testimony that you talk about the cerebral spinal fluid samples, which are highly valued, can be stored in freezers for years, and that you and your NIH colleagues had every reason to believe that they would still be available. So it is your understanding that the samples which NIH investigators may have an interest in are generally preserved and made available for possible research along the lines in which they were drawn from, extracted from? DR. MOLCHAN. That is a bigger area of policy than I am involved with, and again, I think some of those policies are being evolved and worked on. MR. STUPAK. Okay. You also state in your testimony that "As research for Alzheimer's disease has progressed, the need for spinal fluid samples has increased as they may shed light on treatment options for this increasingly prevalent disease. All available scientific resources are indeed to fight AD." Could you elaborate further for the committee and for our understanding on how the loss of these samples and data could hamper further research or publications in the field of this research? DR. MOLCHAN. Okay. Are we talking about my specific study samples? MR. STUPAK. Yes. DR. MOLCHAN. Since another study was being planned by this Alzheimer's clinical trial consortium that I work with now, it didn't make sense that I had done a similar study and we couldn't get information from it. MR. STUPAK. The data, in other words? DR. MOLCHAN. That we couldn't get data. I was able to give some of my experience as far the safety of the drug that we were using and everything in these Alzheimer's patients, and that was helpful, but it really would have been helpful to have more data on the effects on memory of what we were doing, as well as especially the spinal fluid because of being part of this new study that they want to do is to look at spinal fluid. It is a big part of helping us to try to understand what is going on in Alzheimer's disease. We can look at various measures in spinal fluid, how those measures react to a drug, for example, tell us something about what is going on, what is going wrong in Alzheimer's. MR. STUPAK. If you know, you took samples from 25 subjects, right? DR. MOLCHAN. Yes. MR. STUPAK. Of those 25 subjects, is there still partial of that 25 cc's left for all 25 or are some of them gone, some of them have a little remaining? DR. MOLCHAN. That is what I could never ascertain. From what I understand, Dr. Sunderland sent the last of the samples to a collaborator of ours to measure something that the people planning this next study were interested in, that we were all interested in. I never got a handle on what happened to most of it. MR. STUPAK. Thank you. Thank you, Mr. Chairman. MR. WHITFIELD. Yes, sir. Dr. Burgess, I think we have about 8 minutes left in this vote. Would you like to start asking some questions, or would you prefer to just wait and come back after the next votes? Why don't you go ahead and start, then? MR. BURGESS. Very well. Again, thank you for being here. I kind of know what a lumbar puncture is, but for the benefit of the uninitiated, maybe you could just quickly go through the procedure for us. DR. MOLCHAN. Okay. They really, for one thing, really don't hurt that much, and they-- MR. BURGESS. Well, the Chairman said they took three hours. Now, it may take the Chairman three hours, but it shouldn't take the rest of us. DR. MOLCHAN. He would definitely need more. We used to ask people--well-- MR. WHITFIELD. We could break now. DR. MOLCHAN. Well, let me just go through the procedure. It is a lumbar puncture or a spinal tap, and we withdraw some of the fluid that is in the sac that surrounds the brain and the spinal cord, and that has certain proteins in it that we are interested in. So to withdraw some of this fluid, we introduce a needle in between a couple of vertebra in the lumbar spine in the back. People are usually on their side when doing this, and the area is numbed up with some local anesthetic. We insert the larger needle and withdraw about 25 cc's, which we allow to drip into however many--when I was doing it, about 10 tubes for use for various measurements. MR. BURGESS. So it is a fairly invasive procedure? DR. MOLCHAN. It is invasive. It is very safe and it contributes very much to our work, but yes, it is invasive. It is much more than drawing a blood sample. MR. BURGESS. And in fact, 25 cc's is a fairly generous sample for someone who is used to doing them diagnostically. DR. MOLCHAN. Yes. MR. BURGESS. We would have normally obtained five to 10 cc's. DR. MOLCHAN. That is right, when they did them, um-hum. MR. BURGESS. And perhaps a little bit greater risk for things like headache and other sequella after-- DR. MOLCHAN. That is not well-documented and we actually followed the incidents of headache, and especially in the older people, it is actually quite unusual, but that is the biggest side effect is headache. MR. BURGESS. Now, Mr. Stupak was asking about whether the patients involved in these trials were informed about the lithium trial being concluded or ended and then these samples being used in newer trials. To the best of your knowledge, there was no--that information wasn't given to the patients? DR. MOLCHAN. No. MR. BURGESS. Would that be unusual at NIH? DR. MOLCHAN. Well, we had completed the data collection at least at that point. We had done all the spinal taps we were going to do and the next step would have been to work with some laboratories to measure what we were interested in. So as long as we were focusing on what was said in the consent form, measuring these paired samples on and off drug, then no, that would have been that. If it was going to be used for anything else, I am sure there were procedures that would have to be--you would have to go through. MR. BURGESS. Now, you had samples on 25 individuals in this particular study. Can you give the committee any idea of how many tissue samples, which would include, of course, blood, urine, spinal fluid, other tissues, how many tissue samples are stored just in the intramural portion of the National Institute of Health at any given time? DR. MOLCHAN. On an overall? MR. BURGESS. Yeah, on an overall. DR. MOLCHAN. Yeah, I have no idea. MR. BURGESS. I know I don't either, but it has got to be a lot. DR. MOLCHAN. Yeah, a lot is definitely what you are talking about of blood and urine specimens and cells. A lot. MR. BURGESS. And yet, we have heard it mentioned several times that there should be a centralized databank, if you will, of all of the tissue stored at NIH. Do you think that is even technically feasible? DR. MOLCHAN. Well, it depends how central. With our information technology now, and I know for some projects that we have in the university world that when we collect samples we do want to know what we are collecting and make them available to researchers to maximize their use. So these databases are starting to be built up. Again, it is a big coordinating effort using our information technology. So they are underway and I don't know where they are in the intramural program with that at this point. MR. BURGESS. But in the year 2006, that is just kind of beginning? DR. MOLCHAN. Yes. MR. BURGESS. In 1996, that probably would have been unheard of. DR. MOLCHAN. Yes, most likely. Yes. MR. BURGESS. The fact that there wasn't any centralized database for you to go to to find where your samples were, that wasn't necessarily unusual? DR. MOLCHAN. No. MR. BURGESS. Someone else doing research on diabetes that had blood sugar samples might have the same trouble? DR. MOLCHAN. Yeah, I would be surprised, but yeah, not that I know of. MR. BURGESS. Whose responsibility was it to keep those samples safe and retrievable during your tenure there and then after you left, where did that responsibility get assigned? DR. MOLCHAN. From what I understand and from what I thought, it resided with each laboratory chief who was in charge of the certain projects under which the samples were collected. MR. BURGESS. And that laboratory chief in your section would have been? DR. MOLCHAN. Dr. Sunderland. MR. BURGESS. Can you just tell us a little bit about the lithium study without giving away any trade secrets? DR. MOLCHAN. Yes. There is, actually, one drug company doing a similar study now, too, but-- MR. BURGESS. I mean, lithium doesn't cure Alzheimer's. DR. MOLCHAN. No, it does not. There has been some interesting data in the past few years showing that in cell studies and in mice studies that lithium seems to have some effects that hold off degeneration of neurons, including inhibiting the amyloid plaques and the neurofibrillary tangles. It is very interesting because lithium has never been thought of that way. So with these laboratory studies, it has become more of interest to use to see if we could give lithium and then see what happens, for example, in the spinal fluid to levels of amyloid and to levels indicating the fibrillary tangles to see if we should target drug development along those lines. MR. BURGESS. And that is important, because even though you are not curing Alzheimer's disease, even if you can slow down the course a little bit, that is important as well, isn't it? DR. MOLCHAN. As far as the study we were doing, we were trying to find out more. We know lithium and when we use drugs in this way that they work under certain mechanisms, inhibit certain enzymes and so then we test what we can measure in the spinal fluid and from that, we can ascertain whether that enzyme, for example, is inhibited or not and would we want to work to dis- inhibit it to help Alzheimer's disease, things like that. So it is more mechanism. MR. BURGESS. Do you know, do we know, does the committee know, is it available in our report or do you know the information about what were the samples used for, the samples that were diverted away from the NIH? Do we know what those were used for? DR. MOLCHAN. I don't know. MR. BURGESS. So then to the best of our knowledge, there hasn't been any published data about-- DR. MOLCHAN. Well, there was not after I left the institute, the study wasn't followed up, so no, there were no published data on the effects of lithium on these samples, which they were meant for. MR. BURGESS. Were there any other studies of any type then done on these samples after they were diverted-- DR. MOLCHAN. That is what I don't know. MR. BURGESS. --from your lab? DR. MOLCHAN. I don't know. MR. BURGESS. So we don't have that information? DR. MOLCHAN. I don't have it. I don't know if anybody-- MR. BURGESS. Does anybody have that information? DR. MOLCHAN. The committee staff may have some of it. MR. WHITFIELD. We have some of that information which I can talk to you about as we go over-- MR. BURGESS. All right. MR. WHITFIELD. Dr. Burgess, we have a minute to get over to vote, so when we come back we will recognize you for another 2 minutes. MR. BURGESS. You are too kind, Mr. Chairman. I will delay further questions with that in mind. [Recess] MR. WHITFIELD. The hearing will resume, and at this time, I will recognize Dr. Burgess for his remaining two and a half minutes. MR. BURGESS. Thank you, Mr. Chairman. Dr. Molchan, did Dr. Sunderland ever talk to you about what happened to the samples or the research data from your study? DR. MOLCHAN. Just in e-mails and phone calls. I got the information as related that the samples that he sent to our collaborating scientists was all that was left; that the rest was lost in freezer failures. He did indicate, I believe, that they had been used in--well, I would have to look at the records for sure, but from what I could get at the time, he gave me everything that was left. He mentioned some freezer thaw problems where samples were lost. As far as some data, he mentioned it is old data and everything--he seemed to be under the impression that it was published data, which it wasn't. So I got an incomplete response as to what happened. MR. BURGESS. And just to reiterate for the committee, why were you unable to complete the lithium study? DR. MOLCHAN. I had to leave the NIMH. My time was up there and I had to leave, and at the time wanted to stay in the area. I was committed to stay in the Bethesda area and wanted to stay in the public health service, so I transferred to the FDA. MR. BURGESS. Was there no one in the lab that you sort of signed out to and said this is what I am working on, the taxpayers have invested this much money in this lithium study. Would you please continue it? DR. MOLCHAN. No. MR. BURGESS. Would that be common to do that within a research lab if someone had reason to leave the lab? DR. MOLCHAN. Well, when we were there I was on staff at the NIH clinical center, so I was no longer a fellow or anything, but again, the lab chief--it would have been unusual. That just wasn't part of the procedure. The lab chief had the responsibility for studies ultimately. MR. BURGESS. Was the lithium study something that was assigned to you in the lab, or was this a concept that you had yourself that you-- DR. MOLCHAN. It was something that I wanted to do as an independent project. I had the idea based on some actual laboratory research that I had done years ago. MR. BURGESS. But other people in the lab you discussed the lithium study with, had you convinced anyone that this was worthwhile research, or did everyone else-- DR. MOLCHAN. I thought so. I thought Dr. Sunderland, as well as at the time, the overall branch chief, and it went through, of course, the IRB committee of the NIMH, part of which debates whether it is a rational study to do, if it is worth doing, so yes. MR. BURGESS. Does the committee need to be concerned that there are other studies that are just sort of dropped in mid-stride as people come in and come out of the NIH? DR. MOLCHAN. Well, for clinical studies, I don't think there is any good--I mean, there are a lot of studies started by post- doctorals, perhaps, that some may not be followed up. When someone leaves, I guess many times they go to a university--to another laboratory and bring data with them, so that happens. And as far as an overall plan for what happens, that is beyond my experience. MR. BURGESS. Well, you said in your testimony since Congress has shown an interest in this matter, some progress has been made. Can you elaborate on what you mean by "some progress"? DR. MOLCHAN. Well, the NIH has instituted some trans-NIH policies on trying to better keep track of these samples, for one thing, and I was also able to get some additional data that I needed, just some basic demographic data on the subjects that we had the spinal fluid on so I can include that in a publication. MR. BURGESS. Very well. Mr. Chairman, you know, I would just point out that we do talk about having some sort of centralized databank and I think that is a wonderful thing, but you know, in 1996, 1997, I don't know how feasible that was and in my experience in working in labs, I mean, you have got a refrigerator full of stuff and not everyone knows what all is contained therein and the importance thereof. I don't mean that that is right, if it sounds like the NIH is well on the way to remedying and rectifying that problem, but I just wonder about our ability to draw conclusions on a practice from 10 years ago when quite frankly, the computer database technology just may not have existed to keep track of what realistically may have been several million tissue specimens contained at the NIH. I yield back. MR. WHITFIELD. Thank you, Dr. Burgess, and of course, that is what we are going to be focused on as we move forward, and tomorrow we will have some other witnesses, including the Director of the National Institute of Mental Health. At this time, I recognize Mrs. Blackburn for 10 minutes. MRS. BLACKBURN. Thank you, Mr. Chairman. Dr. Molchan, thank you, and thank you for your patience with allowing us to go over and vote and then come back. I will tell you that I am not a physician like Dr. Burgess, and not been involved in any of the research projects like he has, but I am very typical of a lot of Americans in that I have lost a loved one to Alzheimer's. And through that, have watched some of the research and some of the progress and some of the--I guess you would call them near-misses in your community. And I have found this really quite interesting to read through the materials for this hearing, and I appreciate very much your stepping forward, and working with us. You are making the information aware, but I don't have to tell you, whether it is the NIH or any number of other Federal agencies, there is an arrogance that exists within the bureaucracy, a lack of respect that does exist for, I think, this body and for our oversight and for our desire to be certain that the taxpayers' money is appropriately spent. And I think it was quite appropriate that the Chairman of this committee, Mr. Barton, mentioned trust when he made his opening remarks, because it is a loss of trust in the NIH and how they spend their funds, and as we have the head in here, it is something that we are going to be discussing and visiting with him about. A couple of questions I want to go back to, and I feel like I have got a page of notes here as you have talked and given your comments today. You mentioned that the comment was made you were told that you didn't find out exactly what had happened, that the loss of the samples was attributed to freezer loss and that nothing seemed to make sense. Now, who was it that told you that? Was it Dr. Sunderland or someone that worked with him? DR. MOLCHAN. Dr. Sunderland, yes, in e-mails, yes. MRS. BLACKBURN. Okay. So he himself-- DR. MOLCHAN. Yes. MRS. BLACKBURN. --told you that, and you know that didn't seem right, because you know you are not going to lose that much through freezer burn, if you will-- DR. MOLCHAN. Correct. MRS. BLACKBURN. --or-- DR. MOLCHAN. Or whatever reason. I just know how carefully we kept track of them when I was there. MRS. BLACKBURN. Okay. DR. MOLCHAN. And if there was a freezer failure, there would have been some documentation of that, dates and which samples were lost, and there is just nothing specific. MRS. BLACKBURN. And I would imagine that the NIH with these freezers runs them from an operational standpoint that you have a generator backup so that you are never down, and you have got a flush point to move over in case you were to lose power, you would immediately go to a generator? DR. MOLCHAN. I haven't dealt with these freezers for a long time, but they are quite technical and backed up and-- MRS. BLACKBURN. As I would imagine and we would expect. DR. MOLCHAN. A record of the temperature every 24 hours and-- MRS. BLACKBURN. Okay. When I had stepped out of the room, I think that you were mentioning to our Chairman the material transfer process. Were you giving a description of what that material transfer process was? DR. MOLCHAN. I was probably explaining that I really--from my job back then at NIMH and my job now--I really haven't dealt with those, so I would have to--there is a whole staff at NIH now to help people deal with those, because it is getting more complex. MRS. BLACKBURN. Okay. Now, Mr. Chairman, do we have something in writing that describes for us the process by which samples would be transferred within NIH and then to actually leave the jurisdiction of NIH? Do we have that in writing? Is there a document that we have received or should we request that from our witness? MR. WHITFIELD. Just a minute. I will ask our counsel here. MRS. BLACKBURN. And at the same time, do they have in writing a review process by which they would go back and review why a sample was requested? MR. WHITFIELD. We have material transfer agreements. We have copies of that, and it is in the binder. It is Exhibit #2. Then we have Exhibit #38 is NIH technology transfer in U, an explanation of that, and then of course, tomorrow, as you know, we are going to have a number of panels here, three panels and everyone will be from NIH or has been. We will be able to get to that in more detail then. MRS. BLACKBURN. Okay. Dr. Molchan, I think you are familiar with those transfer processes, and would you agree that those and that the review, is it substantial, does it give you enough coverage, is there enough review if samples are requested? DR. MOLCHAN. The samples of materials transfers? MRS. BLACKBURN. Yes. DR. MOLCHAN. I really have not dealt with them in any detail so I can't-- MRS. BLACKBURN. Okay. Let me move on then. Dr. Sunderland in his relationship with Pfizer, would that be--from your vantage point, would you see that as being a normal or abnormal relationship for a researcher from NIH? DR. MOLCHAN. Again, I don't have the details of the relationship, and haven't been in contact with Dr. Sunderland in years. I can't comment since I don't know. MRS. BLACKBURN. Just from other researchers. And then also, is it a normal practice for NIH researchers who are working on a project to go and speak and be paid for the speeches for different pharmaceutical companies and then to be invited into relationships with those companies? DR. MOLCHAN. As far as I know, it is not, and again, it never entered my area of activity or interest, especially since I was at the Food and Drug Administration, so I was totally out and divested in everything. MRS. BLACKBURN. Okay. And then do you know if there is an oversight process and who would be involved in that process that would be checking the relationships with the NIH researchers? DR. MOLCHAN. I don't know. MRS. BLACKBURN. And you never had anyone come to you and question a relationship that you had? DR. MOLCHAN. I haven't been involved in any relationships, you know, since I have been in the Government, especially since I went through the FDA. MRS. BLACKBURN. Okay. DR. MOLCHAN. It is just definitely not allowed there. MRS. BLACKBURN. So while you were aware of others that were paid consulting fees-- DR. MOLCHAN. Yes. MRS. BLACKBURN. --had consulting agreements, you had none of your own? DR. MOLCHAN. No. MRS. BLACKBURN. Okay. All right. Let me ask you this, because I thought your comments to Dr. Burgess were interesting when you were talking about the lithium study and it just dissipated. How much money did you spend on that study through your process? DR. MOLCHAN. Well, I didn't have a budget myself, and what it cost from the budget of the laboratory I was in, Dr. Sunderland's group and at that point, our branch chief, Dr. Murphy, they would have the numbers on that. I don't know what the cost was back then. I just don't, since I didn't have my own budget. MRS. BLACKBURN. Okay. Well, thank you, and Mr. Chairman, I will yield back. MR. WHITFIELD. Thank you, Ms. Blackburn. Mr. Molchan, Mr. Stupak in either his opening statement or questions, mentioned that around $6 million was the estimated cost of collecting these samples. Do you know how that figure was determined or calculated? DR. MOLCHAN. He was talking, I think, of more samples than just involved in my study-- MR. WHITFIELD. Right. DR. MOLCHAN. --so I don't know. MR. WHITFIELD. Okay. And now, what makes spinal fluid so valuable? Just the process of what you have to go through to get it? DR. MOLCHAN. It is not the easiest thing to collect because you have to have special equipment, you have to have special storage for it. A lot of people, especially in this country--it is a common medical procedure done in many hospitals for many different reasons, and it is very safe, but still I guess the vision of having a needle placed into your back doesn't bode well for most people, so we have to convince people that it is worth it. The spinal fluid itself bathes the brain, some of the chemicals in the brain. It is the closest thing you can get to the brain without taking a piece of the brain. MR. WHITFIELD. Absolutely. I also want to ask unanimous consent that we enter into the record a form that is the consent to participate in a clinical research study, and this actually is a form that has you listed as one of the principal investigators. I don't think we have a copy of this for our record, so I would ask unanimous consent that we enter that into the record. [The information follows:] <GRAPHICS NOT AVAILABLE IN TIFF FORMAT> MR. WHITFIELD. At this time, Chairman Barton, would you like to ask some questions of this witness? CHAIRMAN BARTON. Am I the last to question here? MR. WHITFIELD. Yes, sir. CHAIRMAN BARTON. Okay. I have some questions. They are going to be a little bit more generic. Does the administration at NIH share the committee's concern about lack of a centralized tracking system for human tissue sample collection and maintenance? DR. MOLCHAN. You would have to--again, I am not at that level of policy and administration, so I don't--from what I have seen in e-mails, there is more and more interest in it in general in the research community. CHAIRMAN BARTON. Well-- DR. MOLCHAN. The details of NIH, since that is not my purview-- CHAIRMAN BARTON. Well, let me rephrase the question. DR. MOLCHAN. Yes. CHAIRMAN BARTON. Do you share the concern? DR. MOLCHAN. Based on my recent experience, understanding that these samples were collected several years ago, I think things are getting better, and I have seen movements towards policies and working groups being put in place to start to get some more consistent policies. CHAIRMAN BARTON. All right. What knowledge do you have of these spinal fluid samples: Have you been told what happened to the spinal fluid samples that you were so interested in that you couldn't get access to? DR. MOLCHAN. I guess just from two sources. From Dr. Sunderland, which I just mentioned, that there weren't anymore left. Some of them were lost in freezer thaws, and then from what I understand, the committee found that some of them had gone to Pfizer from the NIMH. CHAIRMAN BARTON. Well, 95 percent that according to committee staff briefings were unused, how many of those, in your opinion, have been misused or inappropriately sent outside of NIH? DR. MOLCHAN. That is what I can't have any documentation of or try to ascertain but never got an answer, other than general answers that they are not there anymore, they were lost. CHAIRMAN BARTON. You are okay with that? DR. MOLCHAN. Well, I wasn't okay with that. That is how we ended up here. CHAIRMAN BARTON. Do you have a solution? DR. MOLCHAN. From my purview, I went through channels for a number of months and then expressed my concerns to the committee, and had done everything I felt I could do. I didn't think I was going to get an answer myself, and thought perhaps the committee might. CHAIRMAN BARTON. You have hardly answered--I gave you a question right off the bat where you could say yes, we need a centralized system for monitoring and tracking our human tissue samples, and you basically told me that was outside your area of expertise; that you really didn't have a position on it. DR. MOLCHAN. Well, it depends on a lot of details on that. I know that when we get into these policy things and at what level, it is a complex question and I think-- CHAIRMAN BARTON. It is not that complex. DR. MOLCHAN. I mean, in a general sense-- CHAIRMAN BARTON. If you don't have a system in place-- DR. MOLCHAN. Right. CHAIRMAN BARTON. --to back it across an agency, you are depending on pure faith that everybody-- DR. MOLCHAN. Of course, there are some systems in place. Again, how--and it is getting more consistent across the various institutes. I just don't know details of that since I am not-- CHAIRMAN BARTON. If you were in charge of the NIH, what would you change about the current system for human tissue sample collection, storage, and inventory, if you were in charge? DR. MOLCHAN. Well, again, the NIH is a big place and I am just one tiny piece of it, and these samples came from 10 years ago. So yes, there needs to be careful documentation of who these samples were taken from and when and for what and the consents, where they go, what data results from them. Hopefully it will be shared among investigators, and I hope a lot of that is underway. I just can't, under oath, I guess I am just not comfortable going into too much detail because it is beyond my experience. CHAIRMAN BARTON. So you have no recommendation? DR. MOLCHAN. Well-- CHAIRMAN BARTON. What did you expect the committee to do when you contacted us? DR. MOLCHAN. Well, I know that there has been some progress made, that there are trans-NIH-- CHAIRMAN BARTON. Is somebody at NIH pressuring you to hold back? DR. MOLCHAN. No. CHAIRMAN BARTON. Are you under any kind of threats? I have given you every opportunity to just absolutely tell us what you think needs to be changed, and you have resolutely refused. That is fine. You don't have to, but my gosh-- DR. MOLCHAN. I just don't know-- CHAIRMAN BARTON. --you are the person who came to us and said we have got a problem. You would think you would have some ideas about how to solve it, other than just say-- DR. MOLCHAN. Yes. CHAIRMAN BARTON. --it is outside of my area of expertise. DR. MOLCHAN. NIH is a big place and there are lots of different labs and different institutes, and I just have no idea of the policies in those places. It is outside of my purview, but yes, of course we need systems to track these things. CHAIRMAN BARTON. How about some penalties if you abuse the tracking system? DR. MOLCHAN. I would hope-- CHAIRMAN BARTON. Do you think it is appropriate that some of your spinal fluid samples went to Pfizer? DR. MOLCHAN. Not unless they were used as indicated in the consent form and from what I have gathered, they were not, so no. CHAIRMAN BARTON. Do you think Dr. Sunderland was truthful and honest with you when you inquired about those samples? DR. MOLCHAN. Well, since I never got a complete answer and we all like to see data evidence, no, that is why I went further up the chain. CHAIRMAN BARTON. All right. Do you believe at least said that he was not truthful and open with you? DR. MOLCHAN. Yes. CHAIRMAN BARTON. What would he have had to have done to have met your requirement that he didn't do? DR. MOLCHAN. Just document, just tell us what happened to the rest of them, whether it was really in freezer failures--that large volume--again, from the careful documentation I knew went on in that laboratory on these types of things, I would have liked to see some documentation of what happened and when and there was just nothing like that. CHAIRMAN BARTON. But to your knowledge today, there is not an acceptable accounting of those samples that were unused, is there? DR. MOLCHAN. Correct. CHAIRMAN BARTON. Are you okay with that? DR. MOLCHAN. No, I have never been okay with it, and I have done what I can do-- CHAIRMAN BARTON. If you were Mr. Whitfield or Mr. Stupak, the Chairman and Ranking Member, would you insist on an accurate accounting of those samples? DR. MOLCHAN. Yes. CHAIRMAN BARTON. Okay. DR. MOLCHAN. Yes. CHAIRMAN BARTON. I guess, Mr. Chairman, that is all the questions I have. MR. WHITFIELD. Thank you, Mr. Chairman. Mr. Stupak, I understand you have a few additional questions? MR. STUPAK. Yes. Doctor, if I may, to your right there is your consent form. You see it right there? DR. MOLCHAN. Yes. MR. STUPAK. And I note first that the form appears to be dated October of '84, so that form is already 22 years old. Have they updated the form since then, do you know? DR. MOLCHAN. These are all 1984. MR. STUPAK. Let me further identify, this is your evaluation of lithium treatment in dementia and Alzheimer's patients. DR. MOLCHAN. That is right. MR. STUPAK. This is your-- DR. MOLCHAN. And these are the details of the consent form that I asked them to sign, that is right. MR. STUPAK. So you don't know if they have updated this consent form since then? DR. MOLCHAN. The template I guess came from 1984, and I don't know. MR. STUPAK. Okay. Let me ask you this, because I asked a lot of questions about consent form and things like that. The consent forms only apply to your specific lithium study, so it raises at least two questions with me. Could the samples then be used for the consortium study on lithium use in Alzheimer's patients--or research, I should say, and the consortium, I mean with the University of Pittsburgh. Do you believe that based on this informed consent, those samples could be used with the consortium at the University of Pittsburgh? DR. MOLCHAN. Since we were using samples on and off the drug of interest to see what the effects were, yes. MR. STUPAK. Okay. Then how could such a specific consent form--because I do agree that it is pretty specific--cover transfer to Pfizer for a non-lithium study? DR. MOLCHAN. It does not, from what I can see. MR. STUPAK. And then there is no way you could bend that to make it cover-- DR. MOLCHAN. No. MR. STUPAK. --Pfizer, unless they are doing something with lithium, right? That is your understanding? DR. MOLCHAN. Yes. MR. STUPAK. Okay. DR. MOLCHAN. That is right. To look at the effects of the drug, yes. MR. STUPAK. Correct, because you deal with a number of the neuro-transmitters there, because--right? And you are looking to see how lithium acts on it? DR. MOLCHAN. That is right, yes. MR. STUPAK. Help me out here, acetocholene? DR. MOLCHAN. Acetocholene. MR. STUPAK. Acetocholene is a brain chemical that serves as a messenger or neuro-transmitter in the brain and lithium does affect that, correct? DR. MOLCHAN. What we have been able to see in more Alzheimer's specific measures having to do with the amyloid that is deposited in the brain, things like that. MR. STUPAK. Right, but that is spelled out pretty well in this study? DR. MOLCHAN. But still we are looking at the effects of lithium on it to see if we should, again, go in the direction of a drug mechanism in the way that lithium works, if we should try to develop something similar with not so many side effects, for example. MR. STUPAK. Thank you. I have nothing further, Mr. Chairman. CHAIRMAN BARTON. Mr.-- MR. WHITFIELD. Yes, Mr. Chairman? CHAIRMAN BARTON. I have just one or two more questions. Dr. Sunderland, who has been subpoenaed to testify before this same subcommittee tomorrow, I believe, we were led to believe is going to plead the Fifth Amendment against self-incrimination, but he may not, but we are led to believe that. In your view, do you think that is an appropriate thing for him to do, in terms of the jurisdictional issues at NIH and responsibilities to be open and transparent in dealings with the public? DR. MOLCHAN. I think NIH scientists should be as open and transparent with the public as possible, and from my experience, generally they are, so yes, they should be. And as far as him taking the Fifth, I don't know his full situation. I am not a lawyer, so I can't comment on that. CHAIRMAN BARTON. Did he ever indicate to you when you were trying to get answers on these same questions that you should just mind your own business or bug off or it wasn't your responsibility anymore? DR. MOLCHAN. Not from him. I got that impression from the NIMH director. CHAIRMAN BARTON. And who is that person? DR. MOLCHAN. Dr. Insel. That was from an e-mail where he indicated that I should, you know--Dr. Sunderland is occupied with plenty of other things right now. Please leave him alone. CHAIRMAN BARTON. I understand how busy that fellow can be. DR. MOLCHAN. Yeah. CHAIRMAN BARTON. What is the general loss associated with freezer melting or whatever the technical term is? Would that normally be like one or two percent or 40 or 50 percent? DR. MOLCHAN. It depends on the sample. I mean, in some of these freezers we have whole brains, for example, and it depends on what you are measuring and it depends on the sample. CHAIRMAN BARTON. Well, in general, wouldn't you expect that high value human tissue samples, especially like spinal fluid that are difficult to obtain, that there would be some fairly elaborate-- DR. MOLCHAN. There are. CHAIRMAN BARTON. --mechanisms and fail-safe-- DR. MOLCHAN. At the time I left the NIMH, there were quite elaborate systems of backup-- CHAIRMAN BARTON. You shouldn't have a high percentage of loss-- DR. MOLCHAN. Correct. CHAIRMAN BARTON. --just from something like that? DR. MOLCHAN. Right. There was backup and alarms, people would be called if there was a failure. CHAIRMAN BARTON. Okay. DR. MOLCHAN. Or if any temperature aberration, you know. CHAIRMAN BARTON. Staff wants me to ask this question. What is the average cost per human subject in an Alzheimer's disease clinical trial? Average cost per human subject in an Alzheimer's disease clinical trial. DR. MOLCHAN. For the Alzheimer's consortium that we deal with at the National Institute on Aging, we have been able to calculate that, and we have records. What did we say, about $12,000 per subject. Now, it depends on the length of the trial and how many tests you do, things like that, but on average for the trials we have done at NIA, it has been $12,000 per subject for what they call direct costs, and it is much more than that when you look at total costs when you are including the research infrastructure and data storage and analysis and other things involved most specifically with research. CHAIRMAN BARTON. What percentage of that is the collection of spinal fluid, do you know? DR. MOLCHAN. No. CHAIRMAN BARTON. Just generally, would it be big percentages, little percentage? DR. MOLCHAN. Well, when we collect spinal fluid--we haven't done it very routinely in studies in the past several years. We used to, and then we fell away from it, and now with the importance of it, we are including it in many more studies now. I just know, for example, for the lithium study that is being proposed for this consortium, the cost is estimated to be $17,000 per patient. CHAIRMAN BARTON. Well, if Dr. Sunderland used some of these spinal fluid samples that we don't know what happened to, we know that 528 subjects were used in his Pfizer project, so based on your knowledge of the spinal fluid sample volume, how much of that missing spinal fluid would be needed for 528 subjects in this Pfizer project study? DR. MOLCHAN. It would--again, how much spinal fluid would he need for--depend on, again, what he was measuring and lots of variables. CHAIRMAN BARTON. But I mean, again, I am not asking you to be accurate to the milliliter. DR. MOLCHAN. Yeah. CHAIRMAN BARTON. But would it have taken half of the spinal fluid or-- DR. MOLCHAN. Oh, from a spinal tap? CHAIRMAN BARTON. Yeah. DR. MOLCHAN. Most of these assays take just a tiny amount, 2, 3 cc's, usually much less. Two or 3 cc's, say, out of the 25. Whether there are some tests out there that need more, I am not sure, but usually it is just a fraction of what we collect during a spinal tap, yes. CHAIRMAN BARTON. I mean, but if he--and I am not saying that he did, okay, this is purely hypothetical. If he totally used these spinal fluid samples that are unaccounted for for this 538 subject project at Pfizer, would that have consumed one-third, one- fourth, one-fifth-- DR. MOLCHAN. I don't know, since I don't know all of his projects that he was doing with Pfizer. CHAIRMAN BARTON. But it would take at least 3 cc's per subject? DR. MOLCHAN. I would think, yes. CHAIRMAN BARTON. When you take a spinal tap from an individual, how much fluid do you get out of that? DR. MOLCHAN. Generally around 25 cc's. CHAIRMAN BARTON. So it would take at least one-eighth. DR. MOLCHAN. It is possible, yes. CHAIRMAN BARTON. Just mathematically we would say-- DR. MOLCHAN. Yes. CHAIRMAN BARTON. --he used an eighth of--that would be a fair-- DR. MOLCHAN. That is a fair estimate. CHAIRMAN BARTON. --guess? DR. MOLCHAN. Yeah, you don't like to put all your spinal fluid in one place, I hope, or send it to one collaborator, and you often want to keep specimens like that that are non-renewable on reserve for future interesting possibilities. CHAIRMAN BARTON. Okay. MR. STUPAK. Mr. Chairman, if I may? CHAIRMAN BARTON. Sure. MR. STUPAK. In the type of research that Pfizer was doing, I understand it is proteomics? DR. MOLCHAN. Proteomics, yes, looking at-- MR. STUPAK. Does that take more fluid than a normal-- DR. MOLCHAN. That is what I--since I am not a laboratory assay person, I think some of those take a little more, maybe a few cc's, but I don't know really details of which proteins they are measuring, so I don't know. MR. STUPAK. But it is fair to say in this type of study or research you are conducting, they would have needed more than normal of the fluid? DR. MOLCHAN. More than normal as opposed to-- MR. STUPAK. In the other testing, compared to the lithium test. DR. MOLCHAN. I think they do need--from what I understand, you need a fairly large volume compared to measuring some other things that were routinely measured. CHAIRMAN BARTON. Pilfered. MR. STUPAK. Thank you. Yield back to the Chairman. CHAIRMAN BARTON. My final question. I asked you earlier what the cost per subject, and you said between $12,000 and $17,000. We really didn't get a good estimate if you know what the spinal fluid cost of that was, but let us assume that it is one- eighth. That would be about $1,500 per subject times 528 subjects, that is close to three-quarters of a million dollars that was used inappropriately. DR. MOLCHAN. Well, the 538 came from a number of different protocols, the 538, and I don't know what was in all those consent forms, for one thing. CHAIRMAN BARTON. If three-quarters of a million dollars of tissue samples were used in a privately funded study, somebody should sign off on that and the Government should be reimbursed for that cost. Do you agree with that? DR. MOLCHAN. Yes, certainly. CHAIRMAN BARTON. Okay. I yield back, Mr. Chairman. MR. WHITFIELD. Thank you, Mr. Chairman. That concludes this section of this hearing, and Dr. Molchan, we appreciate your being with us today. Tomorrow, we will have some witnesses that hopefully will be able to be more specific on suggested protocols as we seek ways to guarantee the tracking of these human tissue samples. Tom Insel, who is the director of National Institute of Mental Health, is one of the witnesses. The Deputy Director for Intramural Research, Michael Gottsman, will be here, in addition to Dr. Trey Sunderland, Dr. Karen Putnam, and Dr. David Friedman. So we will recess this hearing until tomorrow at 10:00 a.m., and Dr. Molchan, thank you again for being with us. [Whereupon, at 4:52 p.m., the Subcommittee was recessed, to reconvene the next day at 10:00 a.m.] HUMAN TISSUE SAMPLES: NIH RESEARCH POLICIES AND PRACTICES WEDNESDAY, JUNE 14, 2006 HOUSE OF REPRESENTATIVES, COMMITTEE ON ENERGY AND COMMERCE, SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS, Washington, DC. The committee met, pursuant to notice, at 10:02 a.m., in Room 2322 of the Rayburn House Office Building, Hon. Ed Whitfield (Chairman) presiding. Members present: Representatives Stearns, Bass, Ferguson, Burgess, Blackburn, Barton (ex officio), Stupak, DeGette, Inslee, and Whitfield. Staff present: Mark Paoletta, Chief Counsel for Oversight and Investigations; Alan Slobodin, Deputy Chief Counsel for Oversight and Investigations; Mike Abraham, Legislative Clerk, Ryan Ambrose, Legislative Clerk; John Ford, Minority Counsel; Jessica McNiece, Minority Research Assistant; and William Garner, Minority Professional Staff Member. MR. WHITFIELD. I would like to call this hearing to order. Yesterday we had one panel of witnesses which was one witness, Dr. Susan Molchan, and today we are continuing this hearing on human tissue samples, NIH research policies and practices, and today we will have three panels of witnesses. First of all, I want to thank all of you for joining us this morning. We made our opening statements yesterday so you are going to be very lucky. You don't have to hear a lot of opening statements today. And I would just make the comment that obviously all of us admire and respect the great work that is done at NIH. It is a premier research institution that is doing a tremendous job in trying to find cures and preventions for all sorts of diseases and it is a premier institution. I want to assure everyone today as the Chairman of this subcommittee, speaking for myself, I am not out to get anyone. But we do think it is essential that this institution with its reputation take all steps necessary to ensure the integrity of its research, particularly when people are donating samples. And we want to remove all possibilities of conflicts of interest or the appearance of conflict of interest. And so that is why we are particularly excited that you are here today and we look forward to the testimony from all of you. On the first panel we have Dr. Thomas Insel, who is the Director of the National Institute of Mental Health at the National Institutes of Health, and we have Dr. David Friedman, who lives in Connecticut, so you will be the first two witnesses, and then in addition to Dr. Insel and Dr. Friedman, I guess accompanying you, Dr. Insel, we have Dr. Donald Rosenstein, who is the Acting Clinical Director at the National Institute of Mental Health. We have Mr. William Fitzsimmons, who is Executive Officer of the National Institute of Mental Health, and then we have Ms. Suzanne Winfield, who is the Technology Transfer Officer at the National Institute of Mental Health, but it is my understanding that Dr. Insel, you will be testifying and these three people will be here to assist if it is necessary. Is that correct? DR. INSEL. That is correct. MR. WHITFIELD. And Dr. Friedman, you will be testifying. As you know, this is an Oversight and Investigations Subcommittee hearing and it is our policy to take testimony under oath, and Dr. Insel, do you or Dr. Friedman have any difficulty testifying under oath today? DR. INSEL. I do not. MR. WHITFIELD. And under the rules of the House and the rules of the committee, you are entitled to legal counsel to advise you, and I would ask, do either of you have legal counsel with you today? DR. INSEL. I do not. MR. WHITFIELD. In just a minute I am going to swear you in, but before I do, I want to ask Mr. Stupak, the Ranking Member, if he would like to make any comments before we get started. MR. STUPAK. No, Mr. Chairman. [Witnesses sworn] MR. WHITFIELD. You are now under oath, and Dr. Insel, we will call upon you for your 5 minute opening statement. STATEMENTS OF THOMAS R. INSEL, M.D., DIRECTOR, NATIONAL INSTITUTE OF MENTAL HEALTH, NATIONAL INSTITUTES OF HEALTH, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES; AND DAVID L. FRIEDMAN, PH.D. DR. INSEL. Thank you very much, Mr. Chairman. I have handed out some testimony which probably would go much more than 5 minutes. In thinking about this, I know you have many questions to ask. We have a lot that we would like to discuss with you, and I think rather than going through those five or six pages, if I can just provide you a very simple statement which I hope will be seen as in essence a statement of the principles that we are here for because I think one of the things that we need to keep our eyes on here is what we are about and why it is so important that we protect the NIH mission. As you mentioned, I am the Director of the National Institute of Mental Health, and this is an agency that has a large extramural component. Ninety percent of what we do is at universities and clinics and hospitals all around the country. We are here to focus on the intramural part, which is ten percent of our effort and it is the part that resides here in Bethesda, Maryland, and the part that we often think of as the jewel in the crown because it is a place for highly innovative, exciting science. But I am also here as a physician and a scientist and I think you need to understand that I am absolutely committed to the mission of the NIH, which is to make discoveries to improve human health. For us, the clinical research which is part of what we do has to be understood as a real partnership and it can only be done because it is a partnership between clinical researchers who work as scientists and physicians and volunteers, research volunteers. These are people who may have illnesses, they may be actually healthy subjects, but they undergo painful and sometimes risky procedures to participate in this important mission that we have at the NIH. We can only do this kind of work, it is just clear to all of us, if we understand that we are committed and the public understands that we are committed to minimizing risk, to protecting privacy and to using this information for the common good. That just has to be a fundamental, and as we think about this, I think you will agree that this whole enterprise that we are involved with really rests on trust. We can't do this without the public trust. We can't do this without your trust and we can't do this without trusting each other to some extent, trusting each other that we will do the right thing. Whenever there is a conflict of interest or even a perceived conflict of interest, this trust is placed in peril and that is the situation that we are in this morning and as we talk about this individual case. There are many policies and there are various levels of review to preclude conflicts of interest and we will go through those I think over the course of the next few minutes, but basically it comes down to one simple principle, and this has to be seen for us as true north. That simple principle is that volunteers, their families, and the public must know that an NIH scientist is working for them and not for anyone else. We cannot allow a scientist or anyone else at NIH to trade his or her public role for private gain. It is very simple. That is the basis from which our ethics policy is built. Dr. Zerhouni sent out another message late last night to remind all NIH employees that that is a fundamental and that has to be understood. Violating this simple principle jeopardizes public trust and everything we stand for at NIH and I will do everything, everything I can to ensure that this does not happen. I look forward to your questions. [The prepared statement of Thomas R. Insel, M.D. follows:] PREPARED STATEMENT OF THOMAS R. INSEL, M.D., DIRECTOR, NATIONAL INSTITUTE OF MENTAL HEALTH, NATIONAL INSTITUTES OF HEALTH, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Chairman and distinguished members of the Subcommittee: I am Dr. Thomas Insel, the Director of the National Institute of Mental Health (NIMH), the component of the National Institutes of Health (NIH), an agency of the Department of Health and Human Services (HHS), tasked with responsibility for developing improved methods of diagnosing, treating, and preventing mental disorders, including schizophrenia, autism, and mood and anxiety disorders. To accomplish this mission, the President and the Congress have provided the NIMH a staff of over 700 employees and a budget of approximately $1.4 billion for Fiscal Year 2006. Nearly 90% of this budget, or almost $1.2 billion, is allocated to the support of biomedical research and research training activities through various grant, contract, and fellowship mechanisms at universities, hospitals, and clinics around the nation. The remaining $160 million per year is used to support a unique and critical intramural biomedical research program on the NIH campus in Bethesda, Maryland. This program was established to provide rapid responses to public health emergencies and to support an environment of innovation and creativity for biomedical discoveries. It is the operation of this intramural research program that is the focus of this hearing today. First, I want to commend the Committee for its interest in NIH and the NIMH. As a public servant, I am well aware of my responsibilities to be a careful and vigilant steward of the public resources entrusted to my care. I know full well that you share my commitment on this point, and that you are working with all of us at the NIH to uphold the highest standards that can rightfully be expected by the public, whose support has enabled us to make remarkable strides in biomedical science. The Subcommittee has been working with NIH on several important issues and concerns that must be addressed, and I welcome the opportunity to cooperate with you as you continue to do so. I have already met with Subcommittee staff on three occasions. Based on the information that has been made available to me, I have taken action to improve our management of clinical samples. I am already taking corrective actions. When I joined the NIMH in November 2002, I was impressed by the level of commitment to patients and families that was clearly so much a part of the culture of the Institute. NIH has been called the "crown jewel" of HHS, and I believe it is such a jewel, among other reasons, because of the dedication and skill of those who conduct research in our intramural program. It is because of them that we have made rapid progress against disabling diseases such as schizophrenia, bipolar illness, and depression. Our stakeholders, especially the families who struggle with these diseases, need us to do all in our power to ensure that science advances as rapidly as possible. At the same time, science-no matter how laudatory its objectives and results-must be conducted with the utmost emphasis on ethical standards, ensuring public trust and support. This is not negotiable. To assure that the science performed at NIMH is of the highest quality and meets stringent ethical standards, there are policies and procedures for the conduct of clinical research, including the management of clinical samples and interactions with industry. We realize that science and public policies change over time and that our rules and procedures must be continually scrutinized for relevance and effectiveness. Although I am confident in the high ethical standards held by our staff, we occasionally find serious problems can occur, as is the case in most large organizations. To the extent that problems result from systemic issues, I am working with the NIH leadership on institutional reforms. At NIMH we recognize that rapid progress requires collaboration, including the exchange of clinical samples, such as blood or cerebrospinal fluid. As these samples are a non- renewable resource from patients involved in clinical studies, the management of these samples is an important aspect of our stewardship of the public trust. The following points may help the Committee understand our approach to this stewardship: <bullet> Federal regulations require both Institutional Review Board (IRB) approval and informed consent, unless waived by the IRB, before a proposed study involving human subjects can begin. <bullet> Samples derived from clinical studies conducted at the NIH are Government property under the responsibility and accountability of chief of the pertinent Laboratory or Branch. The use of these samples is part of our obligation to research volunteers, who are our partners in the discovery process. <bullet> When a trainee or non-tenured investigator leaves the NIMH, the disposition of the clinical samples collected by that junior investigator remains the responsibility of the Laboratory/Branch chief. When the Laboratory/Branch chief leaves, the disposition of the clinical samples becomes the responsibility of the Institute's Scientific Director, who is also the director of the NIMH Division of Intramural Research Programs. <bullet> Collaboration with non-government scientists in the private sector is encouraged as part of an intramural research scientist's official duty. This means that work with industry is done on official time and without non- government compensation. In the past, consultations with industry were permissible, subject to prior approval, if no Federal resources were used, no conflict or subject matter overlap with official duties was identified, and no other ethics concerns were present. <bullet> Investigators with potential conflicts of interest are required to disclose these potential conflicts to the IRB as part of the review process. Like all executive branch employees, investigators who conduct clinical research generally may not participate in official matters in which they have a financial interest. <bullet> The exchange of clinical samples may be an important aspect of collaboration. NIH is enhancing policies pertaining to the handling of human tissue samples and related intellectual property. At NIMH, I believe we have not done enough to ensure that all clinical samples leaving from or arriving at the Institute were adequately monitored. And, while the NIH has a variety of possible written mechanisms (including the Cooperative Research and Development Agreement (CRADA), the Material Transfer Agreement (MTA), and the Simple Letter Agreement(SLA)), these mechanisms have not been used uniformly within the NIMH. <bullet> Current policies require that surplus tissue samples from completed studies need to be monitored through continuing IRB review if the samples are linked to patient identifiers. Although all of our intramural scientists engaged in clinical research are required to complete training in human subjects protections, I am concerned that NIMH investigators may not be uniformly aware of when the use of stored samples requires IRB review. To address these concerns, I have done the following: <bullet> On May 2, 2006, I called an intramural faculty meeting to review current policies and expectations for the handling of clinical samples. <bullet> On May 26, 2006, the NIMH's Acting Clinical Director, Dr. Donald Rosenstein, and I sent a follow-up memo to all intramural scientists to remind them of the current policies and expectations. Specifically, we are requiring that all collaborations involving clinical samples be documented with a written agreement (e.g., CRADA, MTA, or SLA) and that these agreements be cross-referenced for potential conflicts of interest. <bullet> Some of the clinical samples stored at the NIH are from studies that have been completed, meaning that they are no longer enrolling subjects and analyzing data. We are in the process of reviewing all collaborations using stored samples from both active and inactive studies by intramural clinical scientists to ensure that they have appropriate approval and documentation. For stored clinical samples of a completed study, we are requiring all investigators to have an active IRB-approved protocol with continuing review to permit monitoring of these samples. It is important for the Subcommittee to realize that although standards and policies for clinical research and collaborations with the private sector have changed over time, certain rules of conduct have remained constant. NIH scientists have always been required to abide by the general principles of government service. It is a public trust requiring employees to place the public health over private gain. We need to be sure we provide NIH staff with the tools they need to maintain this high standard. Mr. Chairman and members of the Subcommittee, thank you for taking the time to look into these issues at the NIH and the NIMH. We are very proud of the accomplishments that have been made by the NIH, and the fundamental and profound role the agency and its scientists have played in alleviating suffering from disease. We are in a unique position because not only do we have to answer to our primary stakeholders-our patients and their families-but we have to answer to you and to every member of the public who has entrusted us with their hard-earned dollars to carry out NIMH's profound yet straightforward mission: to reduce the enormous burden of mental illness and behavioral disorders through research on mind, brain, and behavior. I will be pleased to answer any of your questions. MR. WHITFIELD. Thank you, Dr. Insel. At this time we will recognize Dr. Friedman for his 5 minute opening statement. DR. FRIEDMAN. Mr. Chairman, members of the committee, thank you for the opportunity to come before you today to discuss the facts relating to the use of cerebrospinal fluid and plasma samples in collaboration between Dr. Sunderland at the NIMH and Pfizer, Inc. I have great respect for the work of this subcommittee and the process of scrutiny underlying this hearing as I believe they will serve to clarify issues and resolve questions about the process and the intent of these key studies. I am appearing before you for several reasons. First, I have firsthand information regarding some of the scientific issues relating to the interaction between Pfizer and Dr. Sunderland. As an employee of Pfizer from 1995 to 2001, I initiated discussions between Dr. Sunderland and Pfizer regarding a possible scientific collaboration to search for and evaluate possible biomarkers of Alzheimer's disease. Second, I have great respect for Dr. Sunderland as a scientist and clinician for his contributions to this important basic research. I also have great respect for each of the key contributors of these experiments including my former Pfizer colleagues and the NIMH staff and associates of Dr. Sunderland who participated in the effort. I also recognize and respect the important contribution of the individual Alzheimer's patients and their respective families who contributed important CSF and plasma samples and underwent extensive testing over the past few decades resulting in the data and samples that are the subject of the discussion today. Finally, I appear today in part because not doing so might be misinterpreted as not supporting the nature, process, and intent of this research effort. I would like to make a few brief comments on the intent of this study as it relates to the issue of biomarkers. The information we sought in this experiment was essential to enable several medically important aspects of Alzheimer's disease treatment, a goal with enormous significance to patients, their families, and society as a whole. We sought to uncover new tools to enable the diagnosis and early detection of Alzheimer's disease. These tools are viewed as essential in the development of new therapeutics due to the current limitations in the unequivocal diagnosis of Alzheimer's disease. We also sought biomarkers for disease progression rate as well as biomarkers to stratify patients by specific disease stages. Last, we sought to identify markers of apparent normal individuals exhibiting no measurable cognitive defect who were at risk of developing Alzheimer's disease as a result of family history and/or genetic predisposition to the disease. This in turn might enable the treatment of cognitively normal yet affected individuals prior to their slow, progressive, debilitating decline. It is important to recognize that these classes of markers serve several important roles. First, they facilitate and enable the proper clinical testing of potential Alzheimer's therapeutics under currently approved FDA guidelines. Second, they may enable and inform regarding the proper clinical diagnosis of patients by the general medical community and may facility the appropriate determination of medication for an individual's specific stage of disease. Finally, when these medications become available, these markers can also serve to enable physicians to individually monitor the response of their patients to ensure optimal and cost-effective treatment. Given the magnitude of the societal burden of Alzheimer's disease now and in the near future, these are important tools to be uncovered and developed. Dr. Sunderland recognized the significance of biomarkers and actively sought to identify biochemical markers as well as other types of markers in order to treat patients more effectively consistent with his role as an academic clinician at the NIMH. This was clearly obvious from his academic publications which in turn was the vehicle through which I as a Pfizer employee initially contacted him regarding an effort to uncover these important tools to assist in the diagnosis and treatment of Alzheimer's patients. Thank you for the opportunity to testify, and I would be happy to answer any questions regarding these issues. [The prepared statement of David L. Friedman, Ph.D. follows:] THE PREPARED STATEMENT OF DAVID L. FRIEDMAN, PH.D. Mr. Chairman and Members of the Subcommittee, thank you for the opportunity to come before you today to discuss the facts relating to the use of cerebrospinal fluid (CSF) and plasma samples in a collaboration between Dr. Sunderland, at the NIMH, and Pfizer Inc. I have great respect for the work of this Subcommittee and the process of scrutiny underlying this hearing, as I believe that it will serve to clarify issues and resolve questions about the process and intent of these key studies. I am appearing before you for several reasons. First, I have first-hand information regarding some scientific issues relating to the interaction between Pfizer and Dr. Sunderland. As an employee of Pfizer, from 1995 to 2001, I initiated discussions between Dr. Sunderland and Pfizer regarding a possible scientific collaboration to search for and evaluate possible biomarkers of Alzheimer's disease. Second, I have great respect for Dr. Sunderland as a scientist and clinician and for his contributions to this important basic research. I also have great respect for each of the key contributors to this experiment, including my former Pfizer colleagues, and the NIMH staff and associates of Dr. Sunderland who participated in this effort. I also recognize and respect the important contribution of the individual Alzheimer's patients and their respective families who contributed important CSF and plasma samples and underwent extensive testing over the past few decades, resulting in data and samples that are the subject of the discussion today. Finally, I appear here today in part because not doing so might be misinterpreted as not supporting the nature, process, and intent of this research effort. I would like to make a few brief comments on the intent of the study as it relates to the issue of biomarkers. The information we sought in this experiment was essential to enable several medically important aspects of treatment of Alzheimer's disease, a goal with enormous significance to patients, their families and to society as a whole. Specifically: <bullet> We sought to uncover new tools to enable the diagnosis and early detection of Alzheimer's disease. These tools are viewed as essential in the development of new therapeutics due to the current limitations in the unequivocal diagnosis of Alzheimer's disease. <bullet> We also sought to identify biomarkers for disease progression rate, essential to conduct cost-effective and efficient clinical drug trials given the heterogeneity of progression rates within this patient population. <bullet> We also sought biomarkers to stratify patients by specific disease stages, knowing that various disease stages were likely to manifest differing components of the disease process and thus the potential to respond to different classes of therapeutics. <bullet> Last, we sought to identify markers of apparently normal individuals, exhibiting no measurable cognitive defect, who were at risk of developing Alzheimer's disease as a result of family history and/or genetic predisposition to the disease. This in turn might enable the treatment of cognitively normal yet affected individuals prior to their slow, progressive, and debilitating decline. It is important to recognize that these classes of markers serve several important roles. <bullet> First, they may facilitate and enable the proper clinical testing of potential Alzheimer's therapeutics under currently approved FDA guidelines. <bullet> Second, they may enable and inform regarding the proper clinical diagnosis of patients by the general medical community, and may facilitate the appropriate determination of medication for an individual's specific stage of the disease. <bullet> Finally, when these medications become available, these markers can also serve to enable physicians to individually monitor the response of their patients to insure optimal and cost-effective treatment. Given the magnitude of the societal burden of Alzheimer's disease now and in the near future, these are important tools to be uncovered and developed. Dr. Sunderland recognized the significance of biomarkers and actively sought to identify biochemical markers as well as other types of markers in order to treat patients more effectively, consistent with his role as an academic clinician at the NIMH. This was clearly obvious from his academic publications, which in turn was the vehicle through which I, as a Pfizer employee, initially contacted him regarding an effort to uncover these important tools to assist in the diagnosis and treatment of Alzheimer's patients. Thank you for the opportunity to testify today. I would be happy to answer any questions you may have regarding this matter. MR. WHITFIELD. Thank you, Dr. Friedman. As you know, this subcommittee had a hearing in 2004 related to this overall issue and as a result of that, NIH and HHS both revisited and dramatically strengthened their ethics regulation, I believe in 2005. The question I would like to start off with, Dr. Insel, for you is, the period we are talking about relating to the spinal fluid transfer to Pfizer and Dr. Sunderland is roughly 1995 to 2001, in that general time frame, but at that time certainly the Institute encouraged collaboration with outside researchers. I mean, you can't do your job without doing that. So I am assuming that throughout the entire NIH, it was totally acceptable for scientists to have outside consulting agreements with private firms. Is that correct or is that not correct? DR. INSEL. Just to clarify, Mr. Chairman, there was encouragement for collaboration with both academic and private scientists but what you have asked about in terms of consulting arrangements was seen as something different than collaboration, so consulting arrangements with anyone outside of the Federal government comes into a very different category. It could be approved but it would require approval and review. MR. WHITFIELD. But it was not unusual for scientists to have outside consulting agreements? DR. INSEL. It was not by any means unusual, but I just want to make sure we are clear about what we are talking about here. You could have both collaboration and you could have consulting agreements, but you couldn't have them with the same agent. MR. WHITFIELD. With the same agent? DR. INSEL. That is right. MR. WHITFIELD. You mean with the same outside party or--is that what you are referring to? DR. INSEL. That is correct. MR. WHITFIELD. Okay. Now, before I get to Dr. Sunderland, let me ask you, any outside agreement that you had as a consultant, there would have to be disclosure of that agreement, I am assuming? DR. INSEL. There is a whole system that would include prior approval--it would include review, approval, and then disclosure would be the minimal. MR. WHITFIELD. So that protocol was already in place that you had to have the review, the approval and so forth, correct? DR. INSEL. That protocol has been in place but I think as you know, beginning in 2005 there was first a moratorium on any outside activities, and in August of 2005 a new set of guidelines that now completely restrict outside activities and they are not permitted with either a pharmaceutical company or with biotech. MR. WHITFIELD. Okay. Dr. Sunderland had executed a material transfer agreement with Pfizer in 1998. He also had the consulting agreement with Pfizer in 1998. At that time was that permissible under existing NIH policies? DR. INSEL. It would not have been approved to have a consulting agreement and an outside activity with the same company at that time. MR. WHITFIELD. Okay. So that would be a violation of the rules and regulations of the NIH at that time? DR. INSEL. I wasn't here in 1998 but what I have been told is that that would not have been approved. MR. WHITFIELD. Was it permissible under NIH policies in 1998 to provide human research samples from NIH labs to a drug company and have a consulting arrangement with that same drug company about those samples? DR. INSEL. No, that is not--that again is the same issue. It is mixing collaboration and consulting, and that is where we get into this overlap between the scientific official duty of one of our researchers and their having some outside income from the same source. MR. WHITFIELD. Right. Now, when we get into patent rights, could you briefly explain--with the caliber of the research that is going on and the new avenues that you are moving, it is not unusual to be involved in new patients. Could you briefly explain the policy of NIH as it relates to patent rights and the involvement of a scientist on your staff with an outside firm regarding patent rights? DR. INSEL. Yes, of course. Ms. Winfield may be able to fill you in more from the Office of Technology Transfer's perspective because she does this for a living, but the opportunity to take discoveries and have them licensed is something that the NIH understands, appreciates, and encourages, and sometimes that can be done through collaborative activity. It is important for the subcommittee to realize that we are encouraging that kind of activity and we are encouraging it as official duty. We want people to work with industry to make discoveries and we want them to do that on government time. In the case where a discovery could be licensed, there is an opportunity to pursue that through the NIH. We have a technology transfer office that has a very well- developed set of guidelines about how that can be done. MR. WHITFIELD. Well, I know that Dr. Sunderland, for example, assigned his patent rights and was listed on Pfizer's patent application as a co-inventor and I know he received no money for that, so was there anything wrong with that? DR. INSEL. So--let me back up a moment. What you are telling me is that he was on a patent application that he received no money for. We have no record in the NIH of a patent application with Pfizer or anyone else from Dr. Sunderland. MR. WHITFIELD. Okay. So you have no record of that? DR. INSEL. So is that a problem for us, for any investigator? Let us take it away from this case, but to discover that someone has an application for a patent either with a private collaborator or without that relates to their official duty as a Federal employee and our agency doesn't know about it? Yes, that is a problem. MR. WHITFIELD. Okay. Why is that a problem? DR. INSEL. So what you are talking about is trying to license for potential commercial gain a discovery or an invention made through your Federal employment, and the Federal government has a stake in that. That is no different than if you as a Member of Congress decided to take something that was part of your official duty as a Congressional Representative and to create it as an invention and try to have it licensed on the side without telling anyone from Congress about that. MR. WHITFIELD. Dr. Friedman, you were with Pfizer from 1995 to 2001? DR. FRIEDMAN. Yes. MR. WHITFIELD. And what were your responsibilities there? DR. FRIEDMAN. I was part of an emerging biomarker group. Because of my doctorate in neuroscience, I had the responsibility for looking for alternative strategies for developing Alzheimer's therapeutics. I was also part of a committee to look for new technologies that were enabling in terms of identifying new biomarkers across a spectrum of disease areas. MR. WHITFIELD. But the research was focused on Alzheimer's? DR. FRIEDMAN. No, the research I was doing was focused on biomarkers for a number of neurological diseases including head trauma and depression. MR. WHITFIELD. And when did you first have contact with Dr. Sunderland about obtaining the spinal fluid from NIH? DR. FRIEDMAN. I first contacted Dr. Sunderland late in 1997, having spent a year on this committee looking for new technologies and realizing that it would be possible to do these experiments. We then sought a partner who had the experience and knowledge and access to samples that would make this project possible, so it was in the fall of 1997. MR. WHITFIELD. And you all entered into a material transfer agreement with him to obtain these samples? DR. FRIEDMAN. Pfizer did in 1998, yes. MR. WHITFIELD. And at that time was there a consulting agreement in effect between Pfizer and Dr. Sunderland? DR. FRIEDMAN. I wasn't part of any of the contracts or negotiations regarding the contracts. Having participated in these types of collaborations before, it was not unusual to have a consulting arrangement as part of a collaboration, but in no way was I part of those discussions. MR. WHITFIELD. So from your personal knowledge, you were not aware of that? DR. FRIEDMAN. Well, not only that, but it wasn't my role as a scientist. MR. WHITFIELD. Right. How would you describe the success of the research that you conducted or that Pfizer was involved in relating to its efforts with NIH on this Alzheimer's project? DR. FRIEDMAN. It is kind of a complicated question because there are multiple facets to that project, and so if you want me to speak in general about those? MR. WHITFIELD. The one with the unknown biomarkers. DR. FRIEDMAN. Okay. So that was the project we did in collaboration with an external partner, Oxford Glycoscience. That project where we are looking for unknown markers has in its technical feasibly not been matched today. It was a huge effort to look for low-abundance markers in cerebrospinal fluid. It led to the identification of over 100 proteins that were likely stage- specific in terms of their release into the cerebrospinal fluid. The follow-up of that process is ongoing. I happen to know by looking at the patent literature that those patents have been updated the past couple of years so it looks as though Pfizer is actively pursuing not only the identification but the validation of those markers which takes several years, so I would view it as being highly successful. MR. WHITFIELD. Right. I see my time has expired, so Mr. Stupak, I will recognize you for 10 minutes. MR. STUPAK. Thank you, Mr. Chairman. Dr. Friedman, you indicated that you are familiar with the MTAs and the CRADAs that they use? DR. FRIEDMAN. No, I indicated I wasn't familiar with them. I wasn't part of the process of-- MR. STUPAK. But I mean, outside of Dr. Sunderland, were you familiar with them? DR. FRIEDMAN. No, I am actually familiar with doing collaborations with academic investigators as part of my role, not just at Pfizer but at other drug companies as well. It is not an unusual process, to say the least. What I indicated-- MR. STUPAK. Let me ask you this. I am looking at Exhibit #15 in the book there, and this is an e-mail and you are carbon-copied on it, and you talked about "pleased that this is working out well both on the scientists' side and on the tech transfer side. We do not need to have an MTA signed prior to CMC on March 12, Julie." And it sort of goes through this meeting, and according to our understanding, you were at this meeting on February 28 when you went to see Dr. Sunderland. Do you remember the meeting of February 20, 1998, when you went to meet-- DR. FRIEDMAN. In general I do. MR. STUPAK. Okay. Do you remember seeing this e-mail? DR. FRIEDMAN. I have seen the e-mail several times, once obviously back then but also subsequently during my prior visits to begin discussions about my role. MR. STUPAK. Well, my concern is, in this e-mail it says, "In discussions regarding Pfizer's needs and Sunderland's needs, Trey indicated he was very happy with MTA arrangement plus consulting that Kathy Smith has been discussing. Trey was also very interested in publication in a reasonable timeframe and that he wanted to make sure that authorship would be based on scientific and intellectual contributions. We indicated agreement on both matters." It seems to me that on February 20 from reading this e- mail and the whole of it, not just the part I quoted, that there were discussions about payment and things that Pfizer would receive from Dr. Sunderland. Is that correct? DR. FRIEDMAN. Yes, it is correct. I was-- MR. STUPAK. Didn't you think that was unusual, that you would be paying a scientist at NIH--or NIMH--excuse me--for his samples and things like that? DR. FRIEDMAN. First of all, this meeting was a mixture of both business and scientific people from Pfizer, so Kathy Monahan was part of the business end of the process. MR. STUPAK. You were there and three other Pfizer scientists? DR. FRIEDMAN. Yes. Correct. I was there because I had initially made contact with Dr. Sunderland and we had established a scientific relationship. We had even begun the discussion about the collaboration prior to-- MR. STUPAK. Yeah, but it says "take care of Pfizer's needs and Sunderland's needs." DR. FRIEDMAN. Those comments were actually from Kathy Smith regarding her interpretation of how the discussions about future-- MR. STUPAK. You didn't think that was what happened at that meeting? DR. FRIEDMAN. No, I didn't say that at all. I can't say clearly that at the time and even until recently, I don't know the difference between a CRADA and an MTA in terms of the implications. MR. STUPAK. What did you understand Dr. Sunderland's need would be then? DR. FRIEDMAN. I didn't try and interpret what his need would be. MR. STUPAK. What were Pfizer's needs at the time of the February 20, 1998, meeting? DR. FRIEDMAN. In a business sense, I don't know. From a scientific sense, we were looking for someone who had well- characterized samples. We were looking for someone who was an expert in the field of Alzheimer's disease because without the combination of those, the efforts that we would put forth would be worthless. MR. STUPAK. Did you think it was odd that you would be paying for these samples? DR. FRIEDMAN. I didn't--in no way did I interpret that we were paying for the samples. We were paying for the opportunity to have a collaboration with Dr. Sunderland and in no way did I know what the specifics of this type of-- MR. STUPAK. So you are saying all this money that Pfizer paid, it wasn't for the sample, it was for the opportunity to work with Dr. Sunderland? DR. FRIEDMAN. That is my interpretation, yes. MR. STUPAK. Really? DR. FRIEDMAN. Exactly. MR. STUPAK. Were samples just thrown in then as good faith or something? DR. FRIEDMAN. I don't think you can put a value on the samples. In spite of the discussion yesterday, I think any attempt to try and do that type of analysis is impossible. MR. STUPAK. The most important thing was really the samples, weren't they? DR. FRIEDMAN. No, the samples are actually useless without the clinical information associated with them. They were-- MR. STUPAK. Couldn't you ake the samples and have them analyzed and have other labs take a look at it depending on what you are trying to do with those samples? DR. FRIEDMAN. Alzheimer's-- MR. STUPAK. There was a great benefit to Pfizer, wasn't there? DR. FRIEDMAN. Alzheimer's is a very complex disease. Knowing what type of patients these came from is almost as valuable as knowing-- MR. STUPAK. Well, not just the patients but also the patient's extended family, blood relatives, some who had-- DR. FRIEDMAN. Absolutely. All of that data is critical to interpret the biochemical measures that we were acquiring as part of this collaboration. We would never have ventured into this without having that complete set of information because otherwise it would be uninterpretable. MR. STUPAK. Do you know if Pfizer had other MTAs or CRADAs with NIH? DR. FRIEDMAN. With NIH? MR. STUPAK. Yes. DR. FRIEDMAN. I wasn't aware, but I wouldn't be surprised if they did. MR. STUPAK. But the samples and the clinical data were transferred under the MTA. In fact, Pfizer was upset because they were transferred in June and they didn't get the data until August, right? DR. FRIEDMAN. I wouldn't characterize it as Pfizer being upset. There were probably members of this project who were more concerned with timelines that were upset about the timing of it but the scientists as part of the project recognized that we would need 6 months at least to acquire that type of biochemical data prior to integrating it with the clinical data to interpret it. MR. STUPAK. You said you are the one who sort of initiated the conversation with Dr. Sunderland and Pfizer, correct? DR. FRIEDMAN. Yes. MR. STUPAK. Before you introduced Dr. Sunderland to other Pfizer officials, did you have conversations with him about what his role would be in this research? DR. FRIEDMAN. Yes. Can I clarify what that conversation was? MR. STUPAK. At any time did money come up during that time as-- DR. FRIEDMAN. No, never. MR. STUPAK. --payment for samples or for data? DR. FRIEDMAN. It was a discussion of a scientific collaboration only. MR. STUPAK. And do you know how money came up in this whole opportunity or this-- DR. FRIEDMAN. I wasn't part of those discussions. MR. STUPAK. Who at Pfizer would be? DR. FRIEDMAN. Kathy Smith would probably be one person. Barry Hess would be another. MR. STUPAK. Dr. Insel, according to our information, Dr. Sunderland is still on the payroll at NIH? DR. INSEL. That is correct. MR. STUPAK. Is any action being taken? DR. INSEL. His case, as you know, was reviewed by the Office of Management Assessment as part of conflict-of-interest concerns. There was a recommendation made, and the case was referred to the Commissioned Corps of the Public Health Service. He is technically a Commissioned Corps employee. MR. STUPAK. So the recommendation was made. When was that--to the Corps? DR. INSEL. I sent that forward I believe on November 21, 2005. MR. STUPAK. Two thousand five. As far as you know, did anything happen on that recommendation? DR. INSEL. I have called and sent notes subsequently and as far as I know, there is no decision made yet by the Commissioned Corps. MR. STUPAK. What was your recommendation? DR. INSEL. My recommendation, which I believe you have in your package, was, I sent forward the Office of Management Assessment review--essentially it was about a five-page set of findings--and I gave them a one-paragraph cover note saying that I was really disappointed, that I thought of Dr. Sunderland as one of the people who had made tremendous contributions to the agency, but that I had been informed by the Office of Management Assessment that civil service employees who had similar levels of violations would have been recommended for termination. MR. STUPAK. So were you recommending his termination? DR. INSEL. I can't actually do that, sir. I don't have the authority. MR. STUPAK. I am not asking if you terminated him. I am asking if you made a recommendation that he should be terminated. DR. INSEL. Well, I tried to explain exactly what I said, that I told them that given the severity and the concerns about these findings, that had he been in the civil service, he would have been likely terminated based on what I had been told by the Office of Management Assessment. They will have to make their own determination about that at the Commissioned Corps. MR. STUPAK. So you don't want to make a recommendation then? DR. INSEL. In fact, I can't. I can't do any more than refer the case-- MR. STUPAK. How about Dr. Molchan? Would you be her supervisor? DR. INSEL. I am not Dr. Molchan's supervisor. MR. STUPAK. If she was to get tenure, would you be involved in the process of whether or not she would receive tenure at NIH? DR. INSEL. She is currently in the National Institute of Aging, so I wouldn't have anything to do with that. If she were to come back to the National Institute of Mental Health and she were a tenured investigator, I would be involved as in my current temporary role as the Acting Scientific Director for about another month. MR. STUPAK. So accountability then would depend upon the institute? The National Institute of Mental Health, that would have had the accountability? DR. INSEL. Let me ask you to unpack that a little bit more in terms of accountability. Accountability for what in this case? MR. STUPAK. Well, in this case let us say Dr. Sunderland. He is a Corps individual so you don't have any control over that, right? DR. INSEL. Right. MR. STUPAK. So who would have accountability over him? DR. INSEL. Well, this is where it gets complicated. So indeed he is an employee of the Commissioned Corps. He is essentially detailed to the National Institutes of Health where he has been for some 24, 25 years. His supervisor is the Scientific Director of the Institute and so-- MR. STUPAK. Of NIH? DR. INSEL. Of NIMH in this case, so we are one of 27 components of the NIH, and NIMH has-- MR. STUPAK. Well, let us put it like this. We find it a little funny on this side of the dais that Dr. Sunderland seems to still be working and does not seem to have any problems but the person who came to the committee with her concerns cannot get tenure at NIH, so we have some real questions here on this side so I guess I am trying to figure out who is making these-- DR. INSEL. Let me tease these two things apart. You say you find it a little funny that he is still there and there is-- MR. STUPAK. I find it suspicious. DR. INSEL. I actually find it a real concern. This has been 2 years since you have given us some information. We have done a very thorough review. We made some recommendations. We made a referral. We are now 7 months down the road and this gentleman is still waiting to find out about his fate. I would separate that from the question about tenure of another scientist. Now, the decision about tenure-- MR. STUPAK. Now, the witness yesterday said that her supervisors were discouraging her from talking to the committee or discouraging her from blowing the whistle, if you will, and then when we find she doesn't receive tenure, I guess that is--we find that suspicious. DR. INSEL. So if I may, if I can back up. MR. STUPAK. Sure. DR. INSEL. She was an employee of the NIMH until I believe 1996, 1997. At that point in time she was not on what we call a tenure track. That is, she was essentially in a training position but an extended one. She did apply for a tenure-track position. It is my understanding that was done in 1997 and that is a competitive process both internal and external. The NIMH, before they would- -or NIH, before they would give tenure to an intramural scientist, they are going to do a very though competitive process to make sure we have got the best and the brightest person. MR. STUPAK. Sure. We find it amazing or amusing that she has 50 co-authored reports with Dr. Sunderland and nothing happens to him but she doesn't get her tenure and she is still waiting, but all those reports for one seem to be beneficial. MR. WHITFIELD. The gentleman's time has expired. MR. STUPAK. Thank you. DR. INSEL. I would be happy to respond to that if I may. MR. WHITFIELD. Okay. DR. INSEL. All I can say that in the tenure process, it may seem ironic to you, but in fact, having 50 papers with your supervisor is not a plus. You are looking for someone who is an independent thinker, who has created their own area of research, who can come in and function independently with their own resources, which is what we define as tenure track or tenure. She certainly was considered in that process. He had nothing--he was not on that committee. Obviously this is done by an independent group. They did have a short list. My understanding is that she didn't make the short list and that happens all too often. MR. WHITFIELD. We will go ahead, and if we have time, we will come back with some more questions. Dr. Burgess, you are recognized for 10 minutes. MR. BURGESS. Thank you, Mr. Chairman. Yesterday during our questioning, the issue came up. Dr. Molchan said that this concept of the lithium study was one that she brought to the lab. It was not a project she was assigned after arriving there. But then when the contract or whatever expired and she leaves the lab, is that unusual then for that particular arm of research just to stop and no one to pick it up and continue that? Would that be the standard operating procedure of the NIH in that type of situation? DR. INSEL. So if I may answer, it is a very in some ways complicated question because it depends on the individual lab and the individual project, but if I can speak to this particular case, I think it is important for the subcommittee to recognize that that was a study that essentially stopped accruing patients early in 1993. She did submit annual progress notes to the Institutional Review Board and the one in 1995 says that she would like to keep the study open even though it has been capped. She hasn't brought anybody else in 2 years because she thinks there may be an opportunity to do additional studies. But in August 8 of 1996, she actually sends a note in the annual note to the board saying that she would like to now terminate the study. She leaves the Institute, as I understand it, in 1997. Now, remember, there has been no additional accrual of patients since 1993 and there have been some papers published in the meantime, but she goes off and leaves for another agency, which is not actually a discovery agency like the NIH, it is a regulatory agency, the FDA, and as she said yesterday, I think my understanding was that this was her project, that wasn't a project of her supervisor's, one that she brought forward, so I don't think in a case like that it would be surprising after the person who had initiated the project decided to terminate it, that no one else decides that they want to pick up on it. That is my understanding of how this took place. MR. BURGESS. If I understood the tone of questioning correctly yesterday from the committee, there seemed to be a sense that there should be some type of central database for sensitive or delicate tissue samples and that someone at NIH should oversee that. Now, I tried to get a sense from Dr. Molchan as to how many blood, urine, tissue samples there might be housed in the various refrigerators and warehouses at the NIH just in the intramural part here in Bethesda, and I really no one would even hazard a guess at a number, but I would suspect those numbers of samples must be in the millions to tens of millions when you think of all of the test- tube racks and all the refrigerators and all the freezers contained in all those buildings out there. Mr. Chairman, I might point out, all those buildings are named for appropriators, not authorizers, as we reconsider the reauthorization of the NIH. But is there currently any type of central way that you keep track of this? If someone were to go out there today and start a spinal fluid study on Alzheimer's patients, would those samples be logged in, coded, and someone keep track of that over time? DR. INSEL. So the investigator, and by that we could be talking about a lab chief or a staff scientist who is involved, would have a tremendous investment in the samples they are collecting, and we would expect them as part of their stewardship to do a very careful documentation of what they have and where they have it and how they are managing it. But the question you are asking, is there a central database, that is, of 54 scientists. Do they at some point pool all of their data on all of their freezers and refrigerators and what they have at any given time? The answer is no. MR. BURGESS. And is it a reasonable expectation that this committee might have that that would ever be in place or is the problem just that the number of samples is just too large? DR. INSEL. I think it is a really interesting question to consider, and I think part of what happens, and as the Chairman said, we are sort of looking at some of these policies through the prism of a single case. We want to make sure that whatever solutions we come up with don't create problems of their own, and what you don't want is a bureaucracy that makes it impossible to move quickly and to make discoveries in an environment like the NIH. At the same time you want to make sure you can manage what you have. As we often say, if you can't measure it, you can't manage it, so you have to know what is there and you have to be able to know what has been used and what still remains. Up until this point, we have left it to the scientists themselves to make those determinations and then we review the scientists based on their stewardship. The question you are asking is, should we put something in place in the era where we have these large lab management software systems? Do we need that? Well, some of the institutes have been doing that and already they are putting those ideas out on the table and trying them out. Some of them have already taken them out on the road a bit to see how they work. Dr. Gottesman may tell you a little bit more about that. It is not as simple as it sounds. It is not necessarily the solution to all problems but I think at this point is one thing that we really want to look at very seriously, and we are in the process right now already in the last few weeks of pulling together inventory of everything we have got, making sure we know what has been used and what hasn't and trying to figure out what would be the impediments to actually coming up with the kind of central database that actually might also articulate with other kinds of clinical research data that we have. So I think there is an opportunity here, and we actually owe it to the subcommittee-- MR. BURGESS. I don't want to interrupt you but my time is going to draw short. There are a couple things--I do want to explore this line of questioning a little further. Not commenting on the rightness or wrongness of what Dr. Sunderland did, would we even be having this discussion if those samples had been used and there had been a blockbuster breakthrough? I mean, myself as a taxpayer and a consumer of medical research at the other end, I might see that as a good thing and a worthwhile thing. Would we even be having this hearing if there had been a wonderful extrapolation of that data and we had seen the onset of Alzheimer's delayed by ten years per patient? DR. INSEL. Well, I appreciate that question. I do think that it is important to separate out scientific collaboration, which was an exciting and promising and I think very useful endeavor, from this question of conflict of interest. I think before you came in, I said the true north here has to be the question of separating out public role, official duty, from private gain, and if that wasn't on the table, then we are here to congratulate Dr. Sunderland on having done I think a really excited scientific collaboration which as you heard from Dr. Friedman may actually bear some really important discoveries for families with Alzheimer's disease. So the question of having actually worked with industry to come up with new biomarkers for Alzheimer's, I think everybody would cheer him on to do that. MR. BURGESS. Would it have been a tragedy if that breakthrough could have occurred and it didn't occur because those samples sat in a freezer somewhere-- DR. INSEL. Absolutely. MR. BURGESS. --for 15 years? DR. INSEL. I think it would be a real mistake to decide based on our considerations of these issues that when you have residual samples from a study like this that has been closed that we just dispose of them because they may have true value and could be used for discoveries. We have examples over and over again-- hepatitis B, hepatitis C, AIDS where it is stored samples that have really brought out fantastic discoveries for human health. There is an opportunity to do that here and it still may happen. MR. BURGESS. Let me ask you this, because it kept coming up yesterday. Is the scientist, the principal investigator under any obligation to go back to the person that sample is collected from and to reissue or redirect permission to study-- DR. INSEL. Reconsent? MR. BURGESS. Reconsent. Yes, sir. Thank you. DR. INSEL. The obligation is not to reconsent but to be very clear is that if you have got samples that are stored for a study that has been terminated, we call those residual samples and you have got them in the freezer and you want to use them again for any purpose that involves research, it is not up to the scientist to decide whether that should go forward or not. We have a very clear new policy in place that says as of just the last few days that we want people to go back to the Institutional Review Board to let them know what new use they would like to make of remaining samples because we don't want to leave that in the hands of the scientist. MR. BURGESS. What would the policy have been when the original lithium study was closed in 1996 or 1997? DR. INSEL. I think the policy there was just very general, and if someone--I could certainly understand how someone could say well, these samples were taken to study neurochemistry in the cerebrospinal fluid, we are studying neurochemistry in the cerebrospinal fluid for Alzheimer's disease and could decide they might be used at that point in time. Remember, now, that would require additional review. MR. BURGESS. But your new policy that is in place would not leave one person as being the final arbiter as to what to do with these potentially very valuable samples; there would be oversight by the Institutional Review Board. Is that correct? DR. INSEL. Precisely. MR. BURGESS. Thank you, Mr. Chairman. MR. WHITFIELD. Thank you, Dr. Burgess. At this time I recognize Ms. DeGette for 10 minutes. MS. DEGETTE. Thank you, Mr. Chairman. Dr. Insel, Mr. Burgess raised some thoughts in my mind about exactly what the IRB process is for these residual tissue samples, and you told him that it would be a shame if the result of this issue was that these samples were just destroyed, and I agree with you, but I also think, and you might know, I have introduced legislation about patient protections and all this, and you said we didn't need a reconsent process. Now, as I understand it, in this situation the original tissue donors did give a consent process and it went through IRB review, right? DR. INSEL. That is correct. MS. DEGETTE. But I am not suggesting a reconsent process, which I think would be impracticable, but I do think in the original consent process, you need to have some kind of informed consent for the donor that these tissue samples may be used later on for some kind of a different experiment or process, correct? DR. INSEL. Absolutely. You will hear later from Dr. Gottesman that we actually have a new policy that will come into place that has to do with having to define what is the disposition of either stored samples or samples following the termination of the protocol. MS. DEGETTE. Right, and this has been a problem not just with the NIH but with other research institutions recently, correct? DR. INSEL. That is right. MS. DEGETTE. And then you said that you would--that for a subsequent study on these tissue samples that might be a different study, they would have to go back to the IRB, right? DR. INSEL. So I should just clarify because I knew we were short on time. There are two options. In some cases--I should say three options. In a case like this where you are studying Alzheimer's disease, I don't know this but it very well may be that, for instance, the subjects in this lithium protocol were all dead by the time that the scientists wanted to use the samples. MS. DEGETTE. Right. DR. INSEL. That puts them into a very different class. MS. DEGETTE. I know, but for a subsequent study. I am not talking about the consent anymore. I am talking about going back to have the subsequent study approved by an IRB. That is what you-- DR. INSEL. Right. It would either need to go--well, it would go to the IRB to ask the question, does this require reconsenting, does this require review, should this even be done, and there may be-- MS. DEGETTE. Just for the threshold issues, would that be a full IRB process or would that be like a threshold IRB process? DR. INSEL. Right. These were questions that we are now entertaining. I might ask Dr. Rosenstein, who is really the expert on the IRB issue, to comment on this because this is exactly the discussion we have been having in the last few weeks. DR. ROSENSTEIN. You are asking about IRB approval of new use of existing samples? MR. WHITFIELD. Excuse me, Dr. Rosenstein. You are going to be testifying, so if you just stand up and raise your right hand. [Witness sworn] MS. DEGETTE. Right. Dr. Insel said in his statement to Mr. Burgess that for a new study using these leftover tissue samples that there would have to be some IRB process. I don't have a lot of time and I have other questions for him, so if you can answer very quickly, I would appreciate it. DR. ROSENSTEIN. The Federal regulations require that research with human samples undergoing initial and ongoing review by an IRB. The question has to do with what the ongoing review is for existing samples. That is the policy that has been clarified. Those regulations have been in place a long time but haven't always been followed as completely as they should be. MS. DEGETTE. And in fact, it wasn't followed in this case, right? DR. ROSENSTEIN. Correct. MS. DEGETTE. Okay. Dr. Insel, let me get back to a couple of other things. Now, I think you testified earlier that you became the director of the National Institute of Mental Health in 2002, correct? DR. INSEL. Yes. MS. DEGETTE. And Dr. Sunderland at that time was a lab chief there, right? DR. INSEL. Yes. MS. DEGETTE. And so you were there in 2004 when we had our hearings in this subcommittee and we found out that there were what we thought then was around $500,000. Now we now it is over $612,000 in unreported payments to Dr. Sunderland, correct? DR. INSEL. I haven't seen all the numbers but I will accept those. MS. DEGETTE. It was lots of money. Can I assume that you know what the payments were for or did you ask him what they were for? DR. INSEL. Well, I have spoken with him about this but I have to clarify that. I had not seen the documentation of any consulting agreements until very, very recently, only in the last few days, so I couldn't tell you what those payments were for at that-- MS. DEGETTE. Why didn't you see the--I mean, if this has been going on for 2 years? DR. INSEL. Right. So, this came out originally in June of 2004 that this subcommittee brought this issue to the NIH and of course all of us began to move into high gear to try to understand what was going on here with some of our scientists. The NIH decided that there should be only one investigation NIH-wide and that investigation would be done by the Office of Management Assessment. We were told specifically not to pursue any of these questions with our own scientists, go back to work, make discoveries, continue to have an impact on human health-- MS. DEGETTE. So you assumed that they were investigated? DR. INSEL. Precisely. MS. DEGETTE. And now why-- DR. INSEL. Well, not only did I assume, I was--this was something that we all agreed would be done by one body. MS. DEGETTE. Right, based on what you were told. I am not being critical. And so when you read those consulting agreements that he had or whatever they were 2 days ago, that was in preparation for this hearing today? DR. INSEL. Right. MS. DEGETTE. Okay. Now, you had testified earlier to Mr. Stupak's question that you went through the whole process of how someone like Dr. Sunderland gets removed and so on and you told Mr. Stupak that you have concerns that it has taken so long to figure out a disposition of his situation. Would that be an accurate statement? DR. INSEL. I have concerns. MS. DEGETTE. What concerns are they? DR. INSEL. Well, it just seems to me that in this case, it has taken 2 years before there is any penalty or any decision made about someone's career. I think that is an awful long time. MS. DEGETTE. Especially in light of these egregious examples here, right? DR. INSEL. Even if we didn't have egregious examples, I really think that in the spirit of due process, we deserve and our scientists deserve resolution of some of these issues so that we can all move on. We need to heal as-- MS. DEGETTE. Have you let your superiors know that, that they need to get some kind of a resolution of this case? DR. INSEL. I have spoken to several people and--but you have to remember, this case is no longer in the National Institutes of Health. It is now sitting elsewhere. MS. DEGETTE. I understand. Now, I want to ask you one more question. You were talking earlier about these computer programs that we have and ways that we can get central registries of these tissue samples and so on, and you were talking about--it sounds like your institute and the other institutes are at the very early stages of talking about how we catalog and cross-reference this data. Would that be accurate? DR. INSEL. So we are at the early stages of talking about it in a systemic way. Individual large labs already do a lot of bar coding, a lot of lab management systems. This is being done. And as you heard yesterday from Dr. Molchan, Dr. Sunderland has an extremely good data-tracking system. That is not the problem here. So there are individual labs who are doing this very, very well. The question is, should we be doing it as an institution, as an agency. Should we have all that rolled into one interoperable database. MS. DEGETTE. Well, I have had many, many short and long conversations with Dr. Zerhouni, and as you know, with the NIH reauthorization, his concept is more centralization of funding and more cross-institute collaboration on research which I happen to agree with that vision, but it seems to me if we don't even have the basic mechanism in place for cataloging and cross-agency utilization of tissue samples, it would be very difficult to have that kind of collaboration without the risk of many situations like the Sunderland situation coming up. Wouldn't you agree? DR. INSEL. I agree with what you are saying but again I want to clarify. I think you have to separate out issues of data tracking, which in some ways are software systems issues that we can do, anyone can do. That is different than the issue of oversight and how you make sure that people are doing the right thing, and that still-- MS. DEGETTE. Right. It doesn't sound like we have got either one in place though. DR. INSEL. Well, what I am telling you is that we are looking at ways of getting the tracking in place but if we simply did that, we wouldn't fix the oversight issue. The oversight issue is the one that really needs to be a focus right now. How do we make sure that people are doing what they are supposed to do. We come back--I think you weren't in the room yet but--to true north, the central principle, public office separated from private gain. MS. DEGETTE. Right. Well, I am with you there. What more do you think we can do to make that oversight a reality because the last set of hearings we had, and I was there, I was on this subcommittee, it was 2 years ago and yet here we are again. DR. INSEL. So Mr. Chairman, if I may, we have actually brought a little diagram to give you some ideas of how we think about doing this, and these have been handed out to you. MS. DEGETTE. Mr. Chairman, I would ask unanimous consent that the copies be made a part of the record. MR. WHITFIELD. Without objection. The copies are being passed out now. [The information follows:] <GRAPHICS NOT AVAILABLE IN TIFF FORMAT> DR. INSEL. I wouldn't want the subcommittee to think for a moment that we don't have anything in place for oversight. We have a great number of ways in which this is done, and what this diagram which you will have copies of demonstrates is that there are actually four different forms of oversight for anybody who wants to begin analyzing a clinical sample. There is the Institutional Review Board that looks at the issues of human subjects' protections. There is a Board of Scientific Counselors that looks at scientific quality and whether these are studies that should be done anyway. There is the Office of Technology Transfer that deals with questions around collaborations. And then the deputy ethics counselor, which has a very important role for making sure that there is no conflict of interest. Now, we had all of these in place in 2004 but what we didn't have then were the arrows. I think if there is a vulnerability in the agency, it was that we weren't well integrated, in some ways in the way you are talking about, Ms. DeGette, around trying to have a single agency approach to many of these issues and what we are building in place now both with electronic systems and with human power as well is making sure that there is cross talk across all of these different elements of oversight so that whenever someone applies for an MTA, there would be an opportunity to know whether it is indeed an outside agency with the same agent and to make sure that this goes to the Institutional Review Board at the same time. MR. WHITFIELD. The lady's time has expired. At this time I recognize Mrs. Blackburn of Tennessee. MRS. BLACKBURN. Thank you, Mr. Chairman. I thank each of you, and I am going to stay right there on the same issue where Ms. DeGette was, so basically what we have got are three primary groups that are doing research. We have the NIH, we have academia, and we have private industry, and what we are trying to figure out is how we have appropriate oversight and not impede science. What I feel like I am hearing from you is well, we have turned a blind eye to what the interface would be between those groups and we have kind of swept those relationships under the rug, and let relationships occur, let payments occur and then until it became an awareness issue, we chose not to address it. Because what I am hearing from you now is well, we didn't have a way to inventory samples but now we are looking at the fact that we need a comprehensive inventory. We have a brand-new policy of going back to the review board and then in February 2005, Dr. Zerhouni established a policy on outside consulting. So Dr. Insel, what I think I am hearing from you is, you didn't think you needed the oversight until it came to the attention that there was misbehavior and wrongdoing and I understand and appreciate your concern for saying that someone deserves the due process through the situation and consideration but our taxpayers hold us responsible for exercising the oversight in being certain that their tax dollars and the research dollars are being spent appropriately and properly. So to go back, we have gone a long way around the horn with Ms. DeGette's question and my question, so, very quickly, how do we have proper oversight and not impede the scientific research? DR. INSEL. Well, I like the way you put your question because that really is finding the sweet spot between making sure that we have the oversight we need but at the same time not putting in too many speed bumps that delay our ability to find a discovery for Alzheimer's disease or autism or another very serious illness, and that is a delicate balance in some cases. Some of the things that-- MRS. BLACKBURN. The action item. You know, let us not talk it to death. What do you see as the bullet points, the action items? DR. INSEL. So for us the action items are new policies, and let me just go through what we have done even in the last few weeks. You know about Dr. Zerhouni's change last year. We put a moratorium on the use of stored samples until we can develop a policy that makes sure that every stored-- MRS. BLACKBURN. Are you slowing down any research by putting that moratorium into play? DR. INSEL. We very well may be. We don't know that yet. We won't know that until we have a full listing of what is there. MRS. BLACKBURN. Okay. DR. INSEL. We are requiring that all collaborations be documented with a written agreement so that we have an opportunity to find out what is being done, where it is being done, and who is responsible, and those things can be reviewed both by, as I showed you with this diagram, by four different groups. And in addition to that, we are making sure that the people within the intramural program, the scientists are fully educated about what it is these new expectations entail. We have had two faculty meetings in the last month to go over these issues. Dr. Gottesman will talk more about some of the things that are being done NIH- wide. MRS. BLACKBURN. So these are all your band-aids? You basically have four band-aids that you are putting in place until you establish a policy? DR. INSEL. Well, we have a policy but it is not necessarily a true fix. MRS. BLACKBURN. And for how many years has the NIH being doing research? DR. INSEL. Clinical research for close to 60 years. MRS. BLACKBURN. For 60 years, so basically you have flown 60 years without a policy? DR. INSEL. We have a number of policies, but you have to recognize that science changes, the needs change-- MRS. BLACKBURN. I recognize that, and I appreciate that, and I have great respect for the work that you do and I want to see that work continue. In that vein, how many employees does the NIH have in total? DR. INSEL. I think the full number is about 17,000 to 18,000 for all of NIH. MRS. BLACKBURN. Seventeen to 18,000, and how many of those are researchers? DR. INSEL. It depends on how you define a researcher. I can tell you-- MRS. BLACKBURN. How many are working in the area of research? DR. INSEL. Well, I would assume that almost all of them are involved in some form or another with the mission of the agency, which is research. I can tell you more from my own institute, NIMH, where we have 700 employees. We have 55 or 54 tenured or tenure-track scientists and we have got another 60 who are staff scientist or staff clinician positions, and there are about another 150 to 200 post-doctoral fellows and other kinds of trainees. MRS. BLACKBURN. Okay. And then your total budget is how much? DR. INSEL. Our budget for the entire institute, NIMH, is roughly $1.4 billion, and about 10 percent of that goes to the intramural program, which is the subject of this hearing, which is about $159 million in the current fiscal year. MRS. BLACKBURN. Okay. Out of that total budget of $1.4 billion for NIMH, what percent goes to research? DR. INSEL. There is about 94 percent, I believe, that goes to research support and there is another six percent that is used--I think that would be right--for research management, which is providing the administrative infrastructure for the research enterprise. MRS. BLACKBURN. All right. Great. Now, in your role as the director at NIH and NIMH, have you ever performed any outside consulting duties? DR. INSEL. No. MRS. BLACKBURN. You have not? Have any of you at the table performed outside consulting duties in your roles? You have never had outside consulting agreements? Dr. Friedman, have you? No? Okay. All right. Going back to Dr. Molchan from yesterday, I found it so interesting that she could have put so much work and energy into a project and then it comes to a stop, so let us look at these researchers and the research projects that you do. You used the term "independent thinkers" in talking about your researchers. How do you prioritize your projects? Do you let the researchers choose what they want to work on? Do you have an agency agenda? Do you all sit down and say we need to work on this, that or the other? So how do you mesh those or are they just flying interconnectedly and just recently brought together? DR. INSEL. So again, we are focusing on our intramural program, this small group, this jewel in the crown that is here in Bethesda which is about 10 percent of what our institute is about. In that case, we have a relatively small group of senior scientists who we look to help generate the most exciting innovative science, high-impact science that they can, and they are reviewed every 4 years, and that review is a very rigorous one in which we bring in a panel from outside the agency to look at three things: how the research is going, is it going in the right directions, are they doing the most cutting-edge work, are they innovative; stewardship, how well is this person actually using the resources that have been given and mentorship, how well are they training the next generation. MRS. BLACKBURN. And how long has that review process been in place? DR. INSEL. Oh, it has been going on at least as long as I know about the agency, which is over 20 years. MRS. BLACKBURN. Okay. Great. And then how often do these researchers choose a project and then choose to terminate a project? Does that happen very often, and do you have a library of research that other researchers can go back to if they are working on some type of research and then they find that there are applications for something that was not intended and they think, well, this may work. What is your library process? DR. INSEL. To answer your first question about how often does someone hit a dry hole, it is often, and that is to be expected. The intramural program is for high-risk, high-yield science. High risk also means that it may often fail, and we actually don't see that as a problem. In terms of having a library of negative results, that library is in publications. That is generally the repository of information for our field and people look to publications both for discoveries and for discoveries that can't be replicated. MRS. BLACKBURN. Very good. All right. I think that is about it, and I have only a couple seconds left so I yield it back. MR. WHITFIELD. Thank you. At this time I recognize Mr. Inslee. MR. INSLEE. Thank you. Dr. Insel, I was looking at this quite colorful chart and it sort of circles a little vial here in the middle and I guess that vial is probably where they put the answers and it only looks half full on this chart, and it sort of I think is a pretty symbolic representation. It just seems to me there is some ambiguity in these processes that needs to be fixed. That is an observation of somebody just new to this issue. But I want to ask you specifically about the situation with Dr. Sunderland. I read in the papers that Mr. Robert Muse, Dr. Sunderland's attorney, said his client "didn't receive a dime for providing anything to Pfizer. He received fees for consulting as for lectures. These are known to NIH and they were permitted under NIH rules." And I guess the question I have is, in the relevant time period, do you have reason to believe that NIH had information regarding the specific financial relationship regarding the collaboration and involving the use of human tissue samples that were originally with NIH? DR. INSEL. If you could clarify when you say the relevant time period. MR. INSLEE. Well, before 2 days ago. How is that? DR. INSEL. I believe some of this information came to the investigation that was done starting in 2004 by the Office of Management Assessment. MR. INSLEE. So before an investigation started, did NIH have information about the specifics of the collaboration that involved apparently use of NIH tissue samples? DR. INSEL. Absolutely. We had an MTA, a materials transfer agreement, between Dr. Sunderland and Pfizer that documented that there was a collaboration to send over 250 cerebrospinal fluid samples for analysis of proteins potentially relevant to Alzheimer's disease. MR. INSLEE. So NIH was aware that there was a financial remuneration going to be paid to Dr. Sunderland? DR. INSEL. Absolutely not. So again, let me clarify. We have to separate here a scientific collaboration which we encourage and which we actually want to promote as long as it is done as one's official duty from an outside activity consulting arrangement with the same agency, which has never been permitted, and in this case was undisclosed. MR. INSLEE. So I want to make sure I understand. The financial remuneration was undisclosed but the transfer of the tissue samples was disclosed? DR. INSEL. Exactly. And bottom line, had he come to you or anyone else at NIH and said at that time my arrangement is that I will be receiving financial remuneration for collaborative services, I will be using NIH tissue samples, they will be removed from NIH physical custody, is that permissible under our rules, what would have happened? DR. INSEL. There is a way to do this and it is something that is called a cooperative research and development agreement. So someone could say--a scientist could say I would like to transfer blood samples to company X and I want company X to pay my laboratory to support a junior investigator. That is actually perfectly permissible and it is also a way of dealing with intellectual property. All of that has been worked out so there are ways to do this but that is not what we are talking about here. MR. INSLEE. Well, in what way is it different? I guess what I am saying is, had permission been sought by this particular investigator for this relationship, would it have been granted? DR. INSEL. Not in the way that it has been described in the staff report. That kind of outside activity, consulting, would not have been permitted for someone who had a collaborative arrangement with the same agency. What I am telling is that if someone wants to collaborate, we try to encourage that. If there is intellectual property at stake, there is actually a way to manage that. That is called this cooperative research and development agreement. That was not actually in the case in this particular example. MR. INSLEE. This may clear to everyone listening to this but I want to make sure I understand it as well. In what way would it have not been consistent with those rules? That it was going to outside the NIH financial structure or was it going to the person who took possession? In what way would it violate those rules? DR. INSEL. Because what this does is, it violates the fundamental principle, which we keep coming back to. It is that overlap between public office and private gain, and the way that we would manage that generally is with this CRADA mechanism and allow someone to actually pursue a collaboration and potentially also seek intellectual property protection or patents. The mechanism used here, the materials transfer agreement, doesn't actually permit that and it is not reviewed in the same way. There is a very extensive review process for a CRADA that ensures that there is no outside activity, that there is no private gain involved. That was not the case. This particular case was not reviewed in that way. MR. INSLEE. What is the sanction if there is a violation of any of the several policies that you have talked about? DR. INSEL. What is the penalty? MR. INSLEE. Yes. DR. INSEL. It is really wide range and it depends on the severity of the penalty and it depends on whether--for instance, in a case, and I don't want to go into this particular case because this is already under investigation elsewhere--but one could imagine that the central question that would be asked is, had someone sought approval, would it have been granted, is there actually an inherent conflict of interest here, those kinds of issues, and so the sanction, the penalty would range from reprimand to suspension to termination, depending on how those particular factors line up. MR. INSLEE. Thank you. MR. WHITFIELD. At this time I will recognize the full committee Chairman, Mr. Barton. CHAIRMAN BARTON. Thank you, Chairman Whitfield and Mr. Stupak, for continuing this hearing from yesterday. My first question, Dr. Insel, what are the inventory control practices now in place at NIH for human tissue sample collection, maintenance and tracking purposes? DR. INSEL. As I said before you came in, Mr. Chairman, we have no central tracking of human tissue samples NIH-wide at this point. CHAIRMAN BARTON. Is there an effort to initiate such a central tracking system? DR. INSEL. There certainly is. There has been a lot of discussion partly as the result of the work of this subcommittee to figure out how we can do this much better, and I can give you a quick rundown of some of the things that we are involved with if that would be helpful. CHAIRMAN BARTON. Now, we are preparing an NIH reauthorization bill which I hope to have public within the next month if not sooner. Is this something that should be a part of that bill? DR. INSEL. I think we need to dig it into a bit. When you think about how you want to specify--I guess it is a question, if you will, of granularity. Do you want to have a tracking system that goes after every freezer, every shelf, every sample and every component of every sample? I think there has got to be a point at which we think about what the details would mean, and as we said earlier in the hearing, finding this sweet spot between promoting discovery and rapid advances in science but not putting in too many speed bumps for the purpose of oversight. We need it, but we need to find a way to do it so that we are still able to make the kind of progress we need. CHAIRMAN BARTON. Well, the staff memo that is attached for this hearing says the current NIH system for human tissue sample collection and maintenance is fairly loose and ad hoc. Is that an accurate assessment? DR. INSEL. I think if you take the pejorative term, pejorative connotation of ad hoc out, I would say that it is ad hoc in the sense that it is delegated to individual scientists who have the greatest investment in their own samples. They have collected them, their careers depend upon them, and I believe as you heard yesterday from Dr. Molchan, even in this case, which has generated so much interest in tissue tracking, you have a scientist who apparently had a pretty good handle on exactly where every sample was and how to find it and he was able to generate 13 years after the fact the samples in question so I am not sure that I would say that it is loose, but I would say that it has been delegated to individual scientists to make sure that they are doing the job the way-- CHAIRMAN BARTON. But you are in agreement that the current system can be improved upon? DR. INSEL. I think the current system needs to be improved upon. The question is how. We want to make sure that our solution doesn't create new problems, and that is why I don't want to rush into this. CHAIRMAN BARTON. All right. Well, let us go on to the next subject. We have one of your researchers, a Dr. Trey Sunderland. Is he still on staff at NIH? DR. INSEL. He is. CHAIRMAN BARTON. Is he on full capability or is he on leave with pay or what is his current status? DR. INSEL. He comes to work. He is getting, as far as I know, full salary and he stills serves as the chief of the geriatric psychiatry branch. CHAIRMAN BARTON. Okay. So he is still on active duty without any-- DR. INSEL. That is correct. CHAIRMAN BARTON. Are you aware that the subcommittee has got documents in evidence that leads us to believe that he has been compensated--I don't know how to put this--in a fashion that doesn't appear to comport with the regulations in place at NIH? DR. INSEL. I have seen the subcommittee documents that suggest that he received outside income for consulting with Pfizer. CHAIRMAN BARTON. Well, we have some evidence that shows $285,000 in payments that appear to be inappropriate, another $200,000 in various expenses that appear to be inappropriate, and over $300,000 in lecture fees that may or may not be appropriate. Now, those numbers add up to three-quarters of a million dollars. What is the average salary of somebody in his position or similar position at NIH right now? DR. INSEL. Well, for someone who is a lab chief, the salaries vary between--generally between $150,000 and $200,000. CHAIRMAN BARTON. So three-quarters of a million dollars in compensation of a questionable nature should raise some eyebrows. It would certainly raise eyebrows if a member of this committee--I think our average salary--it is $165,000. If I had outside income of $750,000 that I didn't report on my financial disclosure statement and came from people who had pending legislation before this committee, I would have an ethics investigation by the Minority party and probably a contested primary and every newspaper in the country asking for my resignation from Congress. Now, I understand that Dr. Zerhouni has changed the ethics requirement at NIH and some of what happened with Dr. Sunderland predated that, so it could well be possible that some of the things that are now unacceptable under the regulations at NIH were acceptable. I haven't seen a timeline so I am not going to say with certainty that all of this compensation that I just enumerated will turn out to be unacceptable, but I will say with certainty that it seems puzzling to me that he still is in his current position with no apparent reaction from the administration at NIH. DR. INSEL. Well, Mr. Chairman, if I may, I think it is important to realize that there has been an extensive investigation. There has been a set of findings. The case has been referred. He is an employee of the Commissioned Corps. The NIH itself doesn't have the authority to either hire or fire Dr. Sunderland. This is done through the Commissioned Corps. CHAIRMAN BARTON. But do you have the authority to put him on leave with pay? You do have the authority to transfer him. DR. INSEL. In fact, my understanding is that his disposition of his--of where he works and what he does is at this point in the hands of the Commissioned Corps, and if I can add-- CHAIRMAN BARTON. What would happen if Dr. Sunderland went out and robbed a bank and then reported to work? Would he report to work with full benefits? DR. INSEL. Let me explain that. Had he been a civil servant and that is the case for over 90 percent of the scientists at NIH, this would have been resolved months ago and we wouldn't be having this discussion at this point in time. We made a recommendation November 21. We made the referral at that point to the Commissioned Corps. It is really out of our hands at this point unfortunately, and I also want to add that I think that fixing this is not enough. I think you need--the subcommittee needs to understand that the NIH intramural program, it is not good enough to just be clean. It has to be Camelot. It has to be the place where no one will have any question about conflicts of interest. There has to be some place in the United States where the public knows that there is no taint, that there is no question, that there is no outside investment that is involved, that this is being done for the public good. This is the place. And for anything to come up that would in any way soil that reputation, we need to take care of it and we need to do more than fix it. We need to actually become the model for how this research is done. CHAIRMAN BARTON. On a bipartisan basis, subcommittee staff has been working on this for at least 6 months and maybe longer, and the report that I get is that Dr. Sunderland failed to provide information, failed to cooperate. What little information that we have gotten, some of it appears to be misleading or intentionally inaccurate, and unless I am briefed by you or your staff later today, Dr. Zerhouni's staff, nobody is disputing, that I am aware of, that some of the payments that I just enumerated are not facts, that we misinterpreted, that there is a misunderstanding. DR. INSEL. So in the-- CHAIRMAN BARTON. And so we have a person who has on the surface suffered no repercussion, none, and you talk about a Camelot. DR. INSEL. You can see why I am frustrated. I should add that in the past few days I understand that his case has been referred to the Inspector General and to the Department of Justice, that that is based not on what the original investigation focused on, which was the questions about whether there was overlap between official duty and outside activities, that is based on some of the new accusations that the subcommittee has brought to our attention. CHAIRMAN BARTON. Well, my time is expired. We want NIH to be the crown jewel. I would much rather be here hosting a hearing where we highlight the breakthroughs on Alzheimer's research. My mother has Alzheimer's. I would love to be commending Dr. Sunderland and yourself and the other doctors for medical research breakthroughs that make life better and easier. It is no fun to be holding this kind of a hearing. DR. INSEL. Amen. CHAIRMAN BARTON. But it is inexcusable that in spite of the public changes that have been made at NIH, there really does not appear to be a cultural change where the institution and the members of the institution condemn the kind of behavior that apparently Dr. Sunderland has exhibited. It is really, really disappointing. And with that, Mr. Chairman, I yield back MR. WHITFIELD. Mr. Bass. MR. BASS. Thank you, Mr. Chairman, and I am not going to use my whole time here and I follow on with what the Chairman has said. This is a little bit reminiscent of the controversy that we had back at the 1990s at Los Alamos when I was on the Intelligence Committee. It was an issue fundamentally of culture and the relationship that the scientific community had with the administrative community. Obviously the issues there were entirely unrelated to what we are talking about here today. I believe that you have addressed the issue of what Dr. Sunderland's status is. Are you aware of the fact that he may not actually be-- there is a possibility that he may not be at his desk all the time, that he has another job somewhere else or he may have a laboratory that he goes to somewhere else? Is that--are you aware of that or not? DR. INSEL. I am not aware that he has any other employment. MR. BASS. All told, you have here allegations at least that there is an impropriety involving outside activity and consulting with the same agent. There are issues of activity that is not allowed. There are disclosure issues. There may be patent issues involved. Do you have specific recommendations for NIH or NIMH with respect to what new policies should be enacted over and above what has been done now that would correct this problem and return this agency to what the Chairman or you referred to rather as the Camelot of research entities? DR. INSEL. Well, I do have a number of ideas about that, and of course, Dr. Zerhouni has spoken to the subcommittee on several occasions to explain many of the things that are being done in the ethics arena starting with first the prohibition against outside activities with either drug companies or pharmaceutical companies, putting in a whole new set of safeguards to make sure that we review any outside activity request, and also having increased requirements for disclosure. All of that was done over the last 18 months. Here we are talking about some slightly different issues which have to do not much or not only with ethical violations but with questions about how our tissue samples and how our clinical samples in general are managed and there I think is part of why I put together this chart for you. I wanted you to see that we do have several independent programs that oversee how clinical samples are used. I think the challenge for us going forward is providing the appropriate integration of those programs and also the appropriate oversight within each one to make sure that people are doing exactly what they have been approved to do. MR. BASS. And it is possible that this collaboration and consulting may have actually been of significant benefit to the research effort. Is that correct or not? Is it possible? I mean, did the work that Pfizer did save NIMH a significant amount of time and money or not? DR. INSEL. I think that is in fact the case. My understanding is that the collaboration was fundamentally to measure two proteins in spinal fluid. The antibody for one of those proteins was a licensed agent that wasn't widely available. It is quite expensive to have those tests done, and Pfizer, as I understand it, agreed to do those free of charge at a tremendous savings to the agency. MR. BASS. Fair enough. I don't have any further questions, Mr. Chairman. MR. WHITFIELD. Mr. Stearns. MR. STEARNS. Thank you, Mr. Chairman. Dr. Insel, you have been at your present position since 2002? DR. INSEL. November 2002. MR. STEARNS. You had mentioned in your conversation with members that you can't manage unless you can measure it, and you went on to say that Dr. Sunderland had a great tracking system. I think those were your words just 20 minutes ago. DR. INSEL. That is right. MR. STEARNS. In this graph, the committee, trying to identify the collected spinal fluids, found that what Dr. Sunderland provided in 2005 is yellow. Molchan provided 97. This is sort of bluish amber. And this is the accounted for samples. Did you know that all these samples are unaccounted for? DR. INSEL. Can I ask what you mean by unaccounted for? MR. STEARNS. Spinal fluid for lithium studies. Do you want me to show you this graph? DR. INSEL. I haven't actually seen the graph but the spinal--so if we are talking about the study done from 1991 to 1993, we had-- there were 25 subjects who were entered into the study. There were 15 who had two lumbar punctures who could have been used for Dr. Molchan's-- MR. STEARNS. Well, the staff is saying this is unaccounted for if you go to that graph. Were you aware that these are unaccounted-for samples that we have no measurement of? DR. INSEL. I really--with all due respect, I think-- MR. STEARNS. Do you dispute what the staff's graph is? DR. INSEL. What I would dispute is what is meant by unaccounted. Dr. Sunderland has not, as far as I know, given away all of his spinal fluid to anyone. There are five -70 freezers-- MR. STEARNS. Let me just finish here. I've got a memo here-- June 20, 2005, to you--oh, this is your original message and "Gottesman's office has been collecting rules, regulations, and policies. We need the following specific information on GPB protocol: a list of samples that went to Pfizer and not a list of names but a list that shows number of samples and protocol so we can link consents to samples, copies of consents." It indicated that, you were sort of aware of all these unaccounted-for samples. In fact, you were asking for it in this memo. Do you want me to show you this memo? DR. INSEL. No, I know the memo that this my-- MR. STEARNS. This is in 2005. Would that be fair-- DR. INSEL. To-- MR. STEARNS. You were asking for the unaccounted samples in 2005? DR. INSEL. Did I use the word "unaccounted" in the memo? MR. STEARNS. I am told by staff you were looking for the data that would help to answer where these unaccountable samples were, so that was over a year ago. DR. INSEL. I--the memo that I sent, the e-mail I sent was that I wanted to find out what was sent to Pfizer and for the protocol-- MR. STEARNS. Well, Pfizer or someone else, not necessarily just Pfizer. DR. INSEL. I am sorry, but in the memo, what I was asking specifically was the request about Pfizer. MR. STEARNS. You said you wanted the number of samples and protocol. DR. INSEL. I wanted the number of samples that would have been sent and the protocols that were involved in those shipments. MR. STEARNS. Are you saying you weren't aware of that large number of unaccounted samples? DR. INSEL. I am saying this to me is a very different topic. You are asking--so my understanding is that Dr. Sunderland had something like 16 protocols in which CSF was collected and many, many samples from across those protocols were sent to Pfizer. I wanted to get a listing of what was sent and what were the protocols that covered it. MR. STEARNS. Well-- DR. INSEL. This is a question about one particular protocol done many, many years earlier that had to do with lithium which I must say is one of the smallest-- MR. STEARNS. Are you saying the graph is wrong? Yes or no. DR. INSEL. I am--I would dispute the term "unaccounted for samples." MR. STEARNS. Okay. DR. INSEL. Because it makes it sound as if they are lost. They are not lost. MR. STEARNS. Well, do you know what happened to them? DR. INSEL. I can tell you that--you know, I-- MR. STEARNS. Can you tell me today what happened to all these samples? DR. INSEL. I can tell you that Dr. Sunderland has a large number of CSF samples that are still stored at the NIH or through one of our contractors. MR. STEARNS. In other words, today you can go back and identify all these samples today if we went out to NIH this morning? DR. INSEL. This is really the core of what we have been talking about for the last hour. I specifically don't have an accounting for every sample. I have an accounting for the protocols. I have an accounting for the-- MR. STEARNS. But the people who work for you have that, is what you are saying? DR. INSEL. Dr. Sunderland would have--I think could account for everything out there. MR. STEARNS. But you said you can't manage unless you measure, but here it has been a year and you can't measure where these unaccounted samples are, so how can you manage it? DR. INSEL. I am disputing your use of the word "unaccounted for." What I am telling you is that there are samples that remain under Dr. Sunderland's supervision. He is expected to be accountable for them. MR. STEARNS. But he has not been accountable to you at this point? DR. INSEL. I have not specifically asked the question of him, where are the five missing tubes of the many tens of thousands that you have from 1991. MR. STEARNS. Let me go to the financial disclosure to the IRB. In part of that review process, Dr. Sunderland filed an exhibit which is 24, and the question which he checked off "no" said, "Have any investigators developed an equity or consultant relationship with a non-NIH source related to this protocol which might be considered a conflict of interest?" He checked off "no" and Dr. Rosenstein, your signature I guess is on here too. Do you think in light of what has happened here that Dr. Sunderland should have checked off "no." Is that in your mind satisfactory that he checked off "no" on this form? DR. ROSENSTEIN. This is a question to me? MR. STEARNS. Yes. DR. ROSENSTEIN. I to this day don't know what the precise details of the relationship between Dr. Sunderland and Pfizer Pharmaceutical is so I can't answer that question definitively. I can say that if an investigator has a consultative relationship that is related to the research, then that should be checked off "yes." MR. STEARNS. Well, let us just go back. Let us say you knew the facts today of his relationship with Pfizer and you had to put your signature down here. Would you have questioned Dr. Sunderland knowing what you know today about his relationship with Pfizer? DR. ROSENSTEIN. Yes, I would have. MR. STEARNS. And what would you have said to him? DR. ROSENSTEIN. I would have asked for a description of the nature of the collaboration and would have brought that back to the full IRB. MR. STEARNS. Would you allow him to vote to check off "no" on this form based upon what you know today? DR. ROSENSTEIN. As you have heard, the samples that were sent to Pfizer were drawn from several different protocols. MR. STEARNS. No, no, I mean just yes or no, if you knew back then what you know today about his relationship with Pfizer, would you have accepted him checking off "no" on this form? DR. ROSENSTEIN. I would have raised the question at the IRB meeting, to ask for an explanation. MR. STEARNS. And you would say Dr. Sunderland, is it possible that yes, you do have a disclosure and you should attach or append to this document your disclosure as what the form is requesting? DR. ROSENSTEIN. Yes. MR. STEARNS. So you would have done that knowing what you know today? DR. ROSENSTEIN. Yes. MR. STEARNS. So Dr. Insel, who is this Commissioned Corps? You are pretty much saying you can't do anything with Dr. Sunderland. You know that he is going to testify and you probably know he is probably going to take the Fifth. That is probably almost a 99 percent conclusion. I mean, I read his lawyer's comment here. He wouldn't come here unless the committee voted and he wants all his rights which I respect and he should have his rights. But I think it is pretty much a foregone conclusion he is going to take the Fifth, and with that in mind, you are saying you have no responsibility for his supervision or his employment or anything, that he has to report to this Commissioned Corps. Is that what you are saying today? DR. INSEL. No. I am his supervisor because-- MR. STEARNS. Are you his supervisor? DR. INSEL. As the Scientific Director, and I am in an acting capacity in that job for the next few weeks-- MR. STEARNS. Because you told Chairman Barton that you could not fire him, you could not do anything. DR. INSEL. That is right. MR. STEARNS. Now you are saying you are his supervisor? DR. INSEL. And I have been--both things are true, so he is a member of the Commissioned Corps which means that he is essentially detailed to the NIH and hiring, firing, and promotion are done through the Corps, but the day-to-day supervision is done at the NIH. MR. STEARNS. Like in a corporation, the hiring and firing is done through the personnel agency but the CEO can fire anybody he wants, and I assume that is what you are so-- DR. INSEL. Are you making a recommendation-- MR. STEARNS. The Commissioned Corps hires him but certainly if you felt his behavior was abhorrent, couldn't you make a recommendation that he be put on administrative leave? DR. INSEL. I have done this. I have--there was an investigation and there was a recommendation that-- MR. STEARNS. What was your recommendation? DR. INSEL. The recommendation to the Commissioned Corps was that we--based on the findings from the Office of Management Assessment, I was deeply disappointed and it appears to be--I think I said the violations were severe enough to merit termination were he in the civil service. I can't tell them what to do but I can tell them what we would do if he were-- MR. STEARNS. So you recommended to the Commissioned Corps that he be dismissed? DR. INSEL. Yes. MR. STEARNS. Okay. Thank you, Mr. Chairman. MR. WHITFIELD. Mr. Ferguson. MR. FERGUSON. Thank you, Mr. Chairman, and I appreciate your having this hearing. I have some questions for Dr. Friedman actually. So Dr. Insel, you can just catch your breath for a few minutes. You have been getting a lot of questions this morning. Dr. Friedman, I didn't want you to feel that you were wasting your time this morning sitting here. But I want to further examine this relationship between Sunderland and Pfizer, and I read your testimony. You seem to know a little bit about that. So let us back up for a second. To your knowledge, did Pfizer contribute resources to the screening effort involved in these NIH samples? DR. FRIEDMAN. They contributed a tremendous amount. There were at least half a dozen people that worked for years as well as enabling technology to be developed. MR. FERGUSON. What kind of commercial products came from that? DR. FRIEDMAN. No commercial products. MR. FERGUSON. Zero? DR. FRIEDMAN. To the best of my knowledge. MR. FERGUSON. Could this type of research, this biomarker research that you have described, is it possible that this research would contribute to development of treatments for Alzheimer's? DR. FRIEDMAN. It is viewed as being critical for development for treatments. MR. FERGUSON. What happens to this kind of research? It gets published, what happens when someone conducts significant research that could have a real impact on-- DR. FRIEDMAN. That is above and beyond what I know about this particular collaboration. MR. FERGUSON. In general. DR. FRIEDMAN. In general, there is a point where it gets published and that usually follows patent applications but it's always dependent on the distribution of the intellectual property which is usually decided in advance. That is my basic understanding of it. MR. FERGUSON. Who reads the publications? DR. FRIEDMAN. Dr. Insel would be a good example of who reads the publications. Everyone in the scientific community does. It is open for input and that is one of the cornerstones of basic science. MR. FERGUSON. So anybody in the health community could benefit from this research of it is published and-- DR. FRIEDMAN. As a matter of fact, I think that they could even benefit from the patent application information as well. There is a tremendous amount of information that is in the public domain and has been for years. MR. FERGUSON. Okay. Now, we know that the rules for these consulting arrangements have changed since this particular instance that we are looking at today, that Dr. Zerhouni has told us about that, that the rules at NIH have changed regarding what is proper since this consultative relationship that Dr. Sunderland had with Pfizer, correct? DR. FRIEDMAN. That is what I am hearing. MR. FERGUSON. How would you characterize this relationship between Dr. Sunderland and Pfizer? DR. FRIEDMAN. With regard to-- MR. FERGUSON. The activities, the consulting relationship that Dr. Sunderland had with Pfizer. DR. FRIEDMAN. I really know very little-- MR. FERGUSON. You played a role in the initial-- DR. FRIEDMAN. What little I know about the consulting arrangement I have learned in the past few months being a part of this process. I am really not in a position to comment. I only know fragmentary information. I mean, if you want me to comment on information that is part of the committee report, it would be a totally uniformed-- MR. FERGUSON. Yes. DR. FRIEDMAN. I will make one comment. From my experience of being part of several collaborations in different drug companies, direct compensation of $25,000 a year for the level of activity that Dr. Sunderland contributed to this project is modest at best. MR. FERGUSON. How do these situations police themselves? Whose responsibility is it to police these-- DR. FRIEDMAN. To police them? MR. FERGUSON. Yes. DR. FRIEDMAN. From the point of view of a drug company? MR. FERGUSON. Sure, or the point of view of any of us looking at these situations. DR. FRIEDMAN. I wouldn't have any clue. MR. FERGUSON. Well, would it be fair to say that a company in one of these situations is relying on the consultant to make a determination whether the relationship is appropriate or not? DR. FRIEDMAN. It would be a guess if I answered that because I really have no knowledge of that. MR. FERGUSON. What is your guess? DR. FRIEDMAN. It is a fair assumption. MR. FERGUSON. Okay. That is all I have. Thank you very much. I yield back. MR. BURGESS. Will the gentleman yield for just a moment? MR. FERGUSON. I would yield to Dr. Burgess. MR. BURGESS. Dr. Friedman, you testified that the markers were in fact critical, the research into the biological markers in Alzheimer's was a critical part of that research? DR. FRIEDMAN. I commented that the identification of these markers is critical to the development of Alzheimer's therapeutics from the point of view of large drug companies. That is part of, as you are well aware, the necessity of tracking any kind of efficacious response to a therapeutic over a reasonable period of time. MR. BURGESS. And yesterday we heard testimony that the samples themselves were by virtue of having all of the genetic and clinical data on the people from whom they were recovered, that the samples themselves were extremely valuable. I guess what is troubling me is, in 1995, 1996 and 1997, you closed the study on an aspect of Alzheimer's that is critical to understand on samples that were widely acknowledged to be very valuable, and as a taxpayer and perhaps one day a consumer of whatever might be developed from this research at NIH, I am more troubled by that than anything else I have heard this morning, that we have a valuable field of study that we are basically just capping and walking away from and leaving in the refrigerator. I think--part of me says we should be grateful that someone picked this up and ran with it. MR. FERGUSON. Are you looking for a response on that because I would like to reclaim my time? MR. BURGESS. I was looking for a response from anyone who feels moved to respond to that. DR. FRIEDMAN. I think Dr. Insel made the point which I will reiterate, good science never disappears. It is picked back up again by other investigators either in the intramural programs or extramural programs. People at drug companies-- MR. BURGESS. Since he is going to reclaim his time, you came perilously close to just disappearing back in the corner of that refrigerator when the study was capped in 1995 or 1996 before someone continued some type of research with those samples on biomarkers which we have admitted are critical to the understanding of Alzheimer's disease, on study samples that were very valuable because genetic contact and makeup of the study participants was known. I am just troubled that that might have not happened. MR. FERGUSON. Now I am really going to reclaim my time. Just in closing, Mr. Chairman, the point I guess I am trying to draw out and confirm is that there can be great value, it seems to me, there can be great value to these collaborative arrangements and that is what it sounds like some of you have said this morning as well. There can be tremendous value to these collaborative arrangements but of course, the ends don't justify the means if they are not being done in a proper way, if they are not being disclosed in a proper way. To this point it seems like the policing for these arrangements has largely fallen to the researcher, the investigator themselves. That is probably why it is a good idea that Dr. Zerhouni is laying out some new guidelines. But we have to--and we all want the Camelot that you had described before, but it is going to be very important for us as we move forward, all of us together, to make sure that we don't lose the value of these collaborative efforts because of the enormous importance of the work that NIH is doing for the health of the Nation, and we just have to make sure that we are doing it in the right way and we have to make sure that we don't have this ends-justify-the-means mentality. I think maybe that is how I would sum up my feeling on this, and I would suspect that may be true for others on the panel as well. Thank you, Mr. Chairman. MR. WHITFIELD. Thank you. Just one other question, then we will get the second panel. Before I ask that question, did you have a unanimous-consent request, Ms. DeGette? MS. DEGETTE. Yes, Mr. Chairman. I am sorry I missed the opening statements yesterday and I would ask unanimous consent that I be allowed to submit mine for the record. I would also ask unanimous consent that the record be kept open for this panel and the next panel and the panel yesterday for the requisite number of days for additional questions if members have-- MR. WHITFIELD. Without objection, so ordered. Dr. Friedman, you had testified that when you initiated this discussion, the initial discussion with Dr. Sunderland, that you were primarily focused on the transfer of the material and so forth and you were certainly not focused on meeting any ethical requirements at NIH. Is that true? DR. FRIEDMAN. Well, it certainly wasn't my responsibility. MR. WHITFIELD. Right, not your responsibility. DR. FRIEDMAN. But it also wasn't true that I was focused on the transfer of the samples. I was focused on setting up, being participatory in setting up a collaboration. MR. WHITFIELD. Collaboration. Okay. Now, I just want to read one excerpt to you. On Exhibit 41, if you would turn to that, this is a letter from Mr. Robert Muse, who I assume is the attorney for Dr. Sunderland, and in that exhibit it is a letter from Dr. Muse to Holly Beckerman-Jaffe, who is the Director of the NIH ethics office, and the reason I want to bring your attention to page 9 is that in this letter, Mr. Muse refers to you, and he said at the time of his inquiry, and I am assuming as you are exploring this coloration opportunity, Dr. Friedman was not aware that Dr. Sunderland had any prior association with Pfizer and that Dr. Sunderland promptly notified Dr. Friedman of this and stated that he would not be able to undertake any actions with regard to the collaboration until such activity was cleared and approved by NIH. Do you remember having that conversation with Mr. Muse? DR. FRIEDMAN. I remember the conversation with Mr. Muse. I don't remember the exact details of that exchange but at no time was I involved in asking about what Dr. Sunderland's responsibilities were. That was his responsibility. Mine was to set up a collaboration and-- MR. WHITFIELD. But Dr. Sunderland did notify you that he would not be able to undertake any action with regard to the collaboration until such activity was cleared and approved by NIH? DR. FRIEDMAN. What I recall is that Dr. Sunderland informed me that he needed to take care of these issues on his own before he could proceed. MR. WHITFIELD. And then he went on to say in turn Dr. Friedman's goal was to make sure that the business, medical, and administrative people at NIH were fully informed. DR. FRIEDMAN. That is certainly not true. In no way did I have any business responsibilities nor would Pfizer have given me those in any way. MR. WHITFIELD. Okay. And as a matter of fact, Dr. Insel, I think you had previously stated that the policy even at that time was that if you were in collaboration with an outside entity and you had a consulting agreement with that entity, that that was not proper. Is that correct? DR. INSEL. That is correct. MR. WHITFIELD. At this time I would like to thank you all very much for your testimony and for being here today. I think this has been quite useful as NIH looks forward, moves forward to deal with these complicated issues and we want to thank you for the great work that you do at NIH and we look forward to continuing working with you as we make an effort to make sure it is a Camelot type of agency. Thank you very much. At this time I would like to call up the second panel, and on the second panel we have Dr. Trey Sunderland and Mrs. Karen Putnam, and if you all would please come forward and sit at the witness table, we would appreciate that. Dr. Trey Sunderland is the Chief of the Geriatric psychiatric branch at the National Institute of Mental Health, and Karen Putnam worked for Dr. Sunderland and is a former employee of the National Institute of Mental Health. They are here with us today pursuant to a subpoena. On May 24, 2006, the subcommittee invited these two individuals to voluntarily testify at this hearing but they declined. On June 3, 2006, Chairman Barton authorized subpoenas to be issued to compel their appearance, which were subsequently served. My understanding is that these witnesses will rely on their Constitutional right not to testify at today's hearing. I believe that this privilege which is the only basis upon which a witness may refuse to cooperate with an inquiry by the House should be personally exercised before the Members as we have done in the past. That is why we have insisted on the appearance of Dr. Sunderland and Mrs. Putnam today. Given the importance of their testimony to this subcommittee's fact-finding processes, I would hope that these individuals might reconsider their decision to invoke this Fifth Amendment right and cooperate with the subcommittee on this critically important investigation. Dr. Sunderland and Mrs. Putnam, you are aware that this subcommittee is holding an investigative hearing and in doing so it is the practice of the subcommittee to take testimony under oath. Do any of you have any objection to testifying under oath today? Okay. As you know, under the rules of the House and the rules of the committee, you are entitled to have legal counsel. Do either of you have legal counsel with you today? MS. PUTNAM. Yes, sir. MR. WHITFIELD. And would you give the name of your legal counsel, please? MR. SHURGLER. Your Honor, David Shurgler. MR. WHITFIELD. David Shurgler. MR. SHURGLER. I am licensed to practice in Washington, D.C. MR. WHITFIELD. Thank you. DR. SUNDERLAND. Robert Muse is my attorney. MR. WHITFIELD. Robert Muse. Okay. [Witnesses sworn] MR. WHITFIELD. Thank you very much. At this time both of you are under oath, and I would ask either one at this time, do you have any opening statement that you would like to make, Dr. Sunderland? DR. SUNDERLAND. No, sir. MR. WHITFIELD. Dr. Putnam? Well, in that case, I would like to ask a question. I would recognize myself. Dr. Sunderland, according to records from Pfizer, the names and other privacy information of about 120 people, patients and volunteers who provided spinal fluid in National Institute of Mental Health studies, were inadvertently disclosed in 1999 shipments by your branch to Pfizer as part of one of the biomarker projects. Now, Dr. Sunderland, did you know about this disclosure and why this occurred? DR. SUNDERLAND. Chairman, as you know, you have had correspondence from my attorney, Mr. Muse, on several issues and I respectfully decline to answer these questions or any further questions based on my Constitutional right. MR. WHITFIELD. So you are refusing to answer the question on the basis of your Fifth Amendment rights, and is it your intent to invoke your Fifth Amendment rights in response to any other questions we may ask you today? DR. SUNDERLAND. It is with great regret that I say yes to that question. MR. WHITFIELD. Then you are excused from the witness table at this time but I advise that you remain subject to the process of the committee and that if the committee's need is such, then we may recall you. DR. SUNDERLAND. Yes, sir. Thank you. MR. WHITFIELD. Dr. Putnam, my next question for you is this. Mrs. Putnam, according to NIH records involving you, there were 2,132 vials of spinal fluid shipped to Pfizer in connection with a known biomarker project representing samples from 538 subjects and about 14 different protocols but there were about 1,100 vials shipped in connection with the unknown biomarkers or discovery research project. Do you know if there is data showing how many subjects are represented in those samples and from what protocol numbers? MS. PUTNAM. Upon the advice of my attorney, I will assert my Fifth Amendment privileges and respectfully decline to answer. MR. WHITFIELD. So Ms. Putnam, you are refusing to answer the question on the basis of the protections afforded to you under the Fifth Amendment of the U.S. Constitution? MS. PUTNAM. Yes. MR. WHITFIELD. And you would invoke that Fifth Amendment right on any additional questions that we may ask you today? MS. PUTNAM. Yes, sir. MR. WHITFIELD. Then you also are excused from the witness table at this time but I would advise you that you remain subject to the process of the committee and that if the committee's need is such, we may recall you at some future time. Thank you. At this time I would like to call up the single witness in the third panel, and that is Dr. Michael Gottesman, who is the Deputy Director for Intramural Research at the National Institute of Health. Dr. Gottesman, thank you very much for being with us today. We appreciate your time. We look forward to your testimony. As you know, this is an investigating oversight committee hearing and it is our process to take testimony under oath. Do you have any objection to testifying under oath today? DR. GOTTESMAN. No, I do not. MR. WHITFIELD. And do you have legal counsel with you today? DR. GOTTESMAN. No, I do not. [Witness sworn] MR. WHITFIELD. You are now under oath, and we recognize you for your 5 minute opening statement. STATEMENT OF MICHAEL M. GOTTESMAN, M.D., DEPUTY DIRECTOR FOR INTRAMURAL RESEARCH, NATIONAL INSTITUTES OF HEALTH, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES DR. GOTTESMAN. Thank you, Mr. Chairman, Mr. Stupak and members of the subcommittee. I am Dr. Michael Gottesman, the Deputy Director for Intramural Research at the National Institutes of Health, an agency with the U.S. Department of Health and Human Services. I am responsible for oversight and coordination of intramural research, training, and technology transfer activities conducted within the laboratories of the 22 intramural research programs of the NIH. So in that sense, I am that person who oversees both the research and the policies that keep NIH researchers out of trouble. The intramural program represents about 10 percent of the total NIH budget, or $2.8 billion in fiscal year 2006. Our 6,000 intramural scientists work in an environment where creativity is encouraged and cutting-edge research is the norm. Discoveries such as the first effective chemotherapy for childhood leukemia and Hodgkin's disease and the use of AZT to treat AIDS were developed in the clinical center at the NIH. The NIH intramural research program could not succeed nor could any scientific endeavor without collaborative interactions between our scientists and scientific investigators in academic research institutions and in private industry. Such collaborations are encouraged as you have heard. Without them, the pathway to discovery would likely be slowed by innumerable obstacles and many of our greatest research achievements might not have occurred. Of course, policies intended to facilitate collaborations between Federal and private-sector researchers must be firmly grounded in ethical principles. The NIH leadership was reminded of the importance of this principle 2 years ago by this subcommittee, and in your recommendations, we realize that there were many areas in which we could improve our oversight. Your recommendations prompted NIH and the Department of Health and Human Services to revisit and dramatically strengthen ethics regulations, as you know, in 2005. New department regulations addressed vulnerabilities of the NIH ethics system by completely banning all personal or outside consulting by NIH scientists with pharmaceutical and biotechnology companies. Private outside consulting on subjects that are the same or similar to an employee's official duties has always been prohibited, as you have heard, even under previous regulations. The events under consideration at today's hearing occurred before these new regulations were issued, the ones absolutely banning consulting arrangements. The subcommittee has understandable concerns about the transfer of human biological samples from NIH to the private sector in connection with the consulting arrangement. NIH shares these concerns. First and foremost, we want to know if important biological samples were transmitted without adequate controls and if human subject protection requirements were met. Second, we want to be sure that our internal controls on biological samples are consistent with all requirements including the regulation governing outside or personal activities. Regardless of the outcome of the multiple reviews concerning this matter, I would like to be perfectly clear about NIH's position. Any attempt to illegally profit from official research activities, especially where human biological materials are involved, is totally unacceptable. Engaging in such an activity is a violation of NIH core ethical principles past and present. We cannot tolerate such behavior since it undermines the credibility of NIH as an unbiased source of scientific information. I am told that the material in question, spinal fluid taken from Alzheimer's disease patients, was provided by an NIH intramural scientist to a pharmaceutical company. This transfer of human tissue samples has raised numerous issues and concerns including the adequate protection of the rights of individuals who participate in clinical trials, alleged conflict of interest, and intellectual-property issues. These areas of oversight involve complex regulations and interactions that need to be clarified, and I think Dr. Insel's chart was just the beginning of the complexity of the issue. What can we do to assure that problems such as this do not recur? In addition to the reforms implemented in our ethics program, we are enhancing policies pertaining to the handling of human tissue samples and related intellectual property. While sharing such materials facilitates and accelerates the scientific process, it is also clear that additional protections must be in place when scientists share tissue samples including blood, serum or, in this case, cerebrospinal spinal fluid. Accordingly, after reviewing our policies and procedures regarding the transfer of such materials, we determined that further clarification is necessary and we are taking the following steps. Number one, NIH will provide guidance to investigators on the different mechanisms including MTAs, letters of collaboration, and cooperative research and development agreements available for entering into collaborations and transferring materials outside of the NIH, and we will require that all transfers of samples derived from human subjects must use a written mechanism so there will be no transfer without a written mechanism. NIH will clarify that in cases involving the transfer of material derived from human subjects, all such written agreements must be accompanied by more-rigorous checks and balances including the review and approval by senior leadership at the relevant institute, so an investigator on his own cannot arrange to transfer these samples. NIH has initiated a comprehensive review of policies across NIH involving MTAs to determine if additional requirements are necessary in the case of MTAs that do not involve the transfer of material derived from human participants. I just want to point out that most of our transfers are of laboratory-derived research tools, pieces of DNA or cell lines or antibodies, things like that, that don't directly affect human subjects or clinical research. NIH has also reviewed its policies governing the use of stored human tissue samples. Stored human tissue samples if identifiable by codes or other identifiers are considered human subjects under applicable Federal regulations. Research uses of previously collected and stored human samples when intramural research program investigators can personally identify the sources must be prospectively reviewed and approved by an institution review board. This is not negotiable. IRBs are charged by Federal regulation 45 CFR part 46 with reviewing research protocols to protect the rights and safeguard the welfare of research participants. When reviewing a proposed new research use of stored samples, an IRB will consider the original research use and carefully consider the informed-consent document in order to determine if the new use is consistent with the original protocol. We believe the process for reviewing uses of stored samples must be clear and rigorous. In order to assure that all NIH intramural research program researchers understand the requirements for the research use of stored samples, the following steps will be or have been taken. A memorandum has been sent to all intramural clinical researchers, clinical directors, and scientific directors clarifying the oversight requirements for the collection and research use of human samples, data and specimens. The clinical center's Medical Executive Committee, which consists of the clinical directors and some other leading scientists in all the institutes, implemented procedures to assure that all clinical center protocols receive continuing NIH IRB review and approval as long as research analyses using coded samples continues. So if a protocol is closed but the samples are still valuable, in order to use those samples you need continuing review and approval by an IRB. NIH will modify its standard MTA form to include language indicating that the transfer of either coded or identifiable samples has been reviewed by an IRB or exempt from IRB review pursuant to 45 CFR 46. All research protocols in which intramural researchers intend to collect and store human samples, specimens, or data must include a detailed description of the intended use of the samples including any proposed future use, even after termination of the protocol. Consent documents must include relevant language. While we cannot anticipate all prospective uses, we want to ensure that research participants have as much information as possible on how their own material will be maintained and used. While these new rules will establish conditions to prevent the recurrence of the problems we have heard about today, in order to be fully successful we must be sure that our staff is fully educated about these rules, that they have the administrative support needed to keep up with the additional paperwork, and we have heard about this issue of overloading people with bureaucratic obstacles and delaying research. This can be addressed with administrative support and these people can also provide expert advice because these are complex regulations. And if the rules are knowingly violated, there will have to be consequences. Science is an ongoing process that requires constant review and adaptation. The same is true for NIH's programs that manage the research enterprise. Many of our adaptations result from internal review. Some ensue from external oversight such as the work of this subcommittee. In either case, NIH leadership understands we must be responsive. Thank you for this opportunity, Mr. Chairman. I would be pleased to answer questions. [The prepared statement of Michael M. Gottesman, M.D. follows:] PREPARED STATEMENT OF MICHAEL M. GOTTESMAN, M.D., DEPUTY DIRECTOR FOR INTRAMURAL RESEARCH, NATIONAL INSTITUTES OF HEALTH, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Good morning Mr. Chairman, Mr. Stupak, and Members of the Subcommittee. I am Dr. Michael Gottesman, the Deputy Director for Intramural Research at the National Institutes of Health (NIH), an agency within the U.S. Department of Health and Human Services (HHS). I am responsible for oversight and coordination of intramural research, training, and technology transfer activities conducted within the laboratories of the 22 intramural programs of the NIH. The intramural program represents about 10 percent of the total NIH budget, or $2.8 billion in Fiscal Year 2006. Our 6000 intramural scientists work in an environment where creativity is encouraged and cutting edge research is the norm. The intramural research program provides unique opportunities and resources to encourage important high-risk, high impact scientific inquiries that may be difficult to pursue in the private sector or academia. Intramural laboratories are regularly subjected to rigorous outside reviews. The NIH Clinical Center is the focal point of the intramural enterprise, where laboratory scientists and clinicians work in close physical and intellectual proximity, providing a unique cauldron for translational and clinical research, with the cost of patient participation covered by the NIH budget. The first chemotherapeutic cures for childhood leukemia and Hodgkin's disease, and the first use of AZT to treat AIDS, resulted from research done at the Clinical Center, the largest research hospital in the country. Of the 19 scientists with medical degrees who have won Nobel Prizes in Medicine in the past 20 years, nine were trained in the intramural program at NIH. The NIH intramural research program could not succeed - nor could any scientific endeavor - without collaborative interactions between our scientists and investigators in academic research institutions and private industry in the course of their official work. Such collaborations are encouraged. Without them, the pathway to discovery would likely be slowed by innumerable obstacles and many of our greatest research achievements might not have occurred. Of course, policies intended to facilitate collaborations between federal and private sector researchers must be firmly grounded in ethical principles. The NIH's leadership was reminded of the importance of this requirement two years ago by this Subcommittee's investigation of consulting arrangements between intramural scientists and companies in the pharmaceutical and biotechnology industries. Your oversight review prompted NIH and HHS to revisit and dramatically strengthen ethics regulations in 2005. New HHS regulations addressed vulnerabilities in the NIH's ethics system by completely banning all personal or outside consulting by NIH scientists with pharmaceutical and biotechnology companies. Private outside consulting on subjects that are the same as or similar to an employee's official duties has always been prohibited, even under previous regulations. The events under consideration at today's hearing occurred before these new regulations were issued. It is a sensitive matter that is still the subject of ongoing review. The events are connected to research on Alzheimer's disease, specifically attempts to identify biomarkers that identify the early presence of the disease. This research is one of the most important areas of investigation regarding Alzheimer's disease and should be pursued with vigor. But the quest for biomarkers by NIH must be conducted according to Federal rules pertaining to human subjects protection, intellectual property, and conflicts of interest. As I understand it, the Subcommittee has specific concerns about the transfer of human biological samples from NIH to the private sector in connection with a consulting arrangement. NIH shares these concerns. First and foremost, we want to know if important biological samples were transmitted without adequate controls and if human subject protection requirements were met. Second, we want to be sure that our internal controls on biological samples support the application and enforcement of all requirements, including the regulation governing outside or personal activities. Regardless of the outcome of the multiple reviews concerning this matter, I want to be perfectly clear about NIH's position. Any attempt to illegally profit from official research activities, especially where human biological samples are involved, is totally unacceptable. Engaging in such an activity is a violation of NIH's core ethical principles, past and present. We can not tolerate such behavior. I am told that the material in question - spinal fluid taken from Alzheimer's disease patients - was provided by a NIH intramural scientist to a pharmaceutical company. This transfer of human tissue samples has raised numerous issues and concerns, including the adequate protection of the rights of individuals who participate in clinical trials, alleged conflict of interest, and intellectual property issues. These areas of oversight involve complex regulations and interactions that need to be clarified. With this principle in mind, on August 25, 2005, HHS, with the concurrence of the Office of Government Ethics, published a final rule governing standards of ethical conduct for NIH employees. The new regulation contains the following additional provisions: <bullet> All NIH employees are now prohibited from engaging in outside employment with pharmaceutical companies and biotechnology companies. <bullet> The extent to which the most senior NIH employees may hold certain types of stock and other financial interests is severely limited. <bullet> The number of employees required to disclose financial interests is significantly expanded. In addition to the reforms implemented in our ethics program, we are enhancing policies pertaining to the handling of human tissue samples and related intellectual property. While sharing such materials facilitates and accelerates the scientific process, it is also clear that additional protections must be in place when scientists share human tissue samples, such as blood, serum, or as in this case, cerebrospinal fluid. Accordingly, after reviewing our policies and procedures regarding the transfer of such materials, we determined that further clarification is necessary. In order that NIH employees understand that formal mechanisms such as Material Transfer Agreements (MTAs) are required when human research materials are transferred, we are taking the following steps: <bullet> NIH will provide additional guidance to investigators on the different mechanisms available for entering into collaborations and transferring materials outside of the NIH. While we thought that the current rules were clear to most scientists, we think it is necessary to clarify that a MTA should be used when transferring materials. Scientists should use research collaborative agreements, or Cooperative Research and Development Agreements (CRADAs), when entering into research collaborations with industry. <bullet> NIH will require that all transfers of samples derived from human subjects must involve a written mechanism - MTA, CRADA, letter of collaboration, or other agreement. Such agreements must be in writing to ensure compliance with all requirements regarding human subjects protections. Further, the use of written mechanisms will permit NIH to track the sharing of clinical samples with outside entities, and monitor compliance with the policy. <bullet> NIH will clarify that in cases involving the transfer of material derived from human subjects, all such written agreements must be accompanied by more rigorous checks and balances, including the review and approval by senior leadership at the relevant Institute. <bullet> NIH has initiated a comprehensive review of policies across NIH involving MTAs to determine if additional requirements are necessary in the case of MTAs that do not involve the transfer of material derived from human participants. NIH policy requires the widespread dissemination of research tools. It is not clear, however, that such enhanced protections should be required for all materials, such as laboratory-produced DNA samples, cell lines, and antibodies, whose main function is to accelerate research. A further analysis is necessary to inform policy development in this area. NIH has also reviewed its policies governing the use of stored human tissue samples. Stored human tissue samples, if identifiable by codes or other identifiers, are considered "human subjects" under applicable Federal regulations. The intramural research program's human research protection program functions under a Federal-Wide Assurance (FWA) with the HHS Office for Human Research Protections (OHRP). Its FWA commits the intramural program to conduct its human subjects research activities consistent with acceptable ethical principles and in compliance with 45 CFR part 46, the regulation governing the protection of human subjects in research. I am responsible for implementing the FWA, and the Office of Human Subjects Research (OHSR) within the Office of Intramural Research serves this purpose. Research uses of previously collected and stored human samples, when intramural research program investigators can personally identify the sources, must be prospectively reviewed and approved by an Institutional Review Board (IRB). IRBs are charged by federal regulation (45 CFR part 46) with reviewing research protocols from the vantage point of protecting the rights and safeguarding the welfare of the research participants. When reviewing a proposed new research use of stored samples, an IRB will consider the original research use and carefully consider the informed consent document in order to determine if the new use is consistent with the original protocol. If the research is subject to regulation by the Food and Drug Administration (FDA) (for example, if an investigational diagnostic test is being studied), then the IRB would also apply FDA regulations. We believe the process for reviewing new uses of stored samples must be clear and rigorous. In order to assure that all NIH intramural research program researchers understand the requirements for the research use of stored samples, the following steps have been or will be taken: <bullet> A memorandum has been sent to all intramural clinical researchers, clinical directors, and scientific directors clarifying the oversight requirements for the collection and research use of human samples, data and specimens. <bullet> The Clinical Center's Medical Executive Committee implemented procedures to assure that all Clinical Center protocols receive continuing NIH IRB review and approval as long as research analyses using coded samples continues. <bullet> NIH will modify its standard MTA form to include language indicating that the transfer of either coded or identifiable samples has been reviewed by an IRB or is exempt from IRB review pursuant to 45 CFR part 46 as determined by OHSR. This step will assist technology transfer staff in determining whether the scientist has adhered to human subjects requirements. <bullet> All research protocols in which intramural researchers intend to collect and store human samples, specimens, or data must include a description of the intended use of the samples; how the samples will be tracked; how they will be stored; what will happen to the samples at the completion of the protocol; what circumstances would prompt the investigator to report to the IRB loss or destruction of samples, and any proposed future use (i.e., use after termination of the protocol). Consent documents must include relevant language. While we cannot anticipate all prospective uses, we want to ensure that research participants have as much information as possible on how their own material will be maintained and used. These steps will help ensure that investigators fully understand NIH requirements for the research use of previously collected, stored human samples, and that proposals for such uses must be approved by an IRB and by OHSR. Science is an ongoing process that requires constant review and adaptation. The same is true for NIH's programs that manage the research enterprise. Many of our adaptations result from internal review. Some ensue from external oversight, such as the work of this Subcommittee. In either case, NIH's leadership understands we must be responsive. Sometimes the problems identified by internal and external oversight are systemic, but sometimes they result from individual behavior. To the extent NIH identifies systemic issues, we will take appropriate action. In the case of individual misconduct, we will seek remediation, including dismissal, where warranted. Thank you for this opportunity, Mr. Chairman. I will be pleased to answer your questions. MR. WHITFIELD. Dr. Gottesman, thank you very much for your testimony, for being here today. First of all, as the Deputy Director for Intramural Research, I would like for you to explain as if you were addressing maybe a rotary club in Leesburg, Virginia, exactly the process that you need to go through if one of your research scientists at, say, the National Institute of Mental Health, came to you with a collaborative agreement and wanted to enter into a collaborative agreement with some third party. Could you just kind of walk us through the steps that would be necessary to clear that? DR. GOTTESMAN. Yes. First of all, when you said come to me, you mean come to the appropriate authority at the institute? MR. WHITFIELD. Yes. DR. GOTTESMAN. So when we engage in cooperative research and development agreements or so-called CRADAs which are the most formal of our agreements with companies, sometimes the agreement is initiated by an investigator who is aware of interests that accompany or somebody else may have in the product. Oftentimes it results from advertising. We actually have adverse research opportunities at the NIH and most often if there is an opportunity to develop a specific idea or a product, our technology development people will meet with the scientists, understand the scope of the project and then advertise that there are opportunities for other companies and then people apply for that opportunity. They are interviewed entirely by the technology development coordinators within the institute. At this point the investigator is not involved in the discussions in terms of negotiations except as an advisor on the scientific aspects of the research. After some discussions, a document is drawn up which describes in detail the nature of the collaboration and we require--there is a whole set of rules that cover what we will allow and what we won't allow. For example, NIH does not do research for hire. If a company wants us to do research for them, we generally won't do that unless it is clear that that is jointly desirable from the point of view of moving science forward. There is a bunch of rules and there is a policy that covers that. I am sure the committee is aware of that. After those discussions, there is review internally, a document which includes a conflict of interest review in which questions are asked about whether the scientists involved in the research have any outside personal activities with the organization, and if they respond that they don't and our review indicates that that is correct and we do--the deputy ethics counselors at each of the institutes does review using Internet searches and so on. MR. WHITFIELD. So they have to file a form that-- DR. GOTTESMAN. There is an extensive document which is the CRADA application form which includes something called a conflict-of-interest evaluation. It is not only a statement by the scientist but it is also a request--there is a process in which the institute actually looks into that statement. As you know, we are developing a better electronic system for tracking all of the different activities of our scientists and that will be an enormous help in researching whether or not there is or is not conflict of interest. If the institute is interested in moving forward, the recommendation goes to a central committee, which is the cooperative Research and Development Committee, which reports to me. There is a chair, and that committee reviews and determines whether the CRADA is in keeping with NIH CRADA policy, makes a recommendation. Sometimes some of the points of the CRADA need to be negotiated. And then that goes back to the institute. It gets renegotiated. It comes back for discussion. Our legal counsel, the Office of Technology Transfer, signs off and I actually sign off centrally as DDIR on all those documents. So it is a very formal, very careful process to guarantee that there is no conflict of interest, that the research is in the interests of the people of this country and that it is scientifically important to move ahead. MR. WHITFIELD. The institute from which it comes is involved, the Office of Intramural Research, and the Office of Technology Transfer is involved. Did I miss any other-- DR. GOTTESMAN. Well, my office, the Office of Intramural Research, the Office of Technology Transfer, the technology development coordinators within the institutes, the committee, the CRADA committee. Many people. And the deputy ethics counselor who reviews the conflict-of-interest statement. So I would say from my point of view, this is a model system. It obviously takes some time to negotiate these agreements and it is possible during that interim period if there is a partner who is anxious to get research going to have a letter of collaboration which precedes a cooperative research and development agreement to allow research to move forward. MR. WHITFIELD. Are there additional safeguards put into these collaborative agreements when human tissue samples are involved or not? DR. GOTTESMAN. Only to the extent that we have human subjects regulations that I have mentioned that kick in. We have a requirement that if there is a CRADA involved in the study, that the IRB be informed about the CRADA, know how the partners are and so on. So we are beginning to make these connections between the different oversight parts of the NIH. MR. WHITFIELD. So the consent forms that donors sign in providing human tissue samples to the institute, they disclose suppose in a rather broad way how this material can be used? DR. GOTTESMAN. So, Mr. Chairman, if you are speaking about the consents that the patients-- MR. WHITFIELD. Yes. DR. GOTTESMAN. Yes. So the process of informed consent has been one of the key features of the development human subjects' protections. I would say that in the early 1990s when many of the protocols were being conducted that we are talking about here, the consent forms were not very specific and in fact, in reviewing for this hearing I looked at some of the consents that were used in this case and it is clear that the patients were being-- that subjects that were being asked to sign off very generally on use of materials. That kind of general language would not be allowed in the current environment. MR. WHITFIELD. Now, there has been some discussion today about the necessity or the need for a central protocol that would extend throughout NIH, particularly relating to human specimen repositories and so forth, but the impression that I get from testimony is that every individual institute already has pretty stringent protocol for tracking this. Is there a real need for a broad policy throughout NIH or is it better to have each institute take care of that? DR. GOTTESMAN. So by tradition, scientists have always controlled their own research activities and resources in the sense that they by virtue of the requirements under our research integrity program are responsible for keeping adequate records for storing samples in an appropriate way, for using these samples under all appropriate rules and regulations. This is part--Dr. Insel mentioned that some of the system is based on trust, and traditionally at the NIH and in all scientific institutions, the individual scientific investigator has had that responsibility. One of the ways in which we are dealing with whether or not those responsibilities are being exercised appropriately is to make sure that samples aren't used for purposes other than the original intended purpose under the approved protocol by requiring all the different steps that I have mentioned. I think probably what is most important is that NIH has been thinking very hard about ways in which we could optimize the use of these samples. As you point out and as many of committee members have pointed out, these are very valuable materials. They are unique in the sense that at no time or place will that individual ever be able to give that sample again if you are looking at a longitudinal study and somebody is being studied over 10 or 20 years and many of the NIH studies are long-term studies. The sample that goes back 20 years as a predictor of a disease to come is a very important sample and not easily reproduced although you could reproduce the whole study. So we really want to be sure that these samples are used appropriately, and one of the things that NIH has been working on in keeping with actually the desire of the whole Federal government to create a much more electronic database for medical and clinical issues is, you know, what does it take to make the system entirely electronic so it is easily queried and you can use materials easily, and we started actually by developing a clinical research information system which took about 5 years and is now in place in the clinical center which tracks all patients' medical records, their test results and their images, their X-rays and so on so that it is possible now, and I invite you all to visit the clinical center, to stand at a patient's bedside and get electronic descriptions of what they are doing. This is the kind of futuristic view of medicine I think NIH is actually taken the lead in this. Each of the institutes is developing in their own way clinical research tools to be able to analyze their specific clinical trials, and as it turns out--I had mentioned we have 22 intramural programs. About 17 of them do clinical research. And the type of clinical research differs substantially amongst the institutes so each has different needs and a few different protocols are being developed. I just spoke to one of our scientific directors who spent 4 years developing a data set, a tracking program for clinical samples, clinical trials, clinical questions that are being asked in the institute within one of the institutes and we talked about the feasibility of making that more generally available and I think that will begin to happen. I think we are still up against a bit of a technical problem. The number of samples involved is overwhelming and we are not talking about, you know, putting bar codes on them as they come in. We are talking about going back 20, sometimes 30 years and we are talking about millions of samples at the NIH. So this is a big task but I think it is a laudable goal both from the oversight point of view and also because what it does is, it makes available these potential data sets to people who have a new idea for research. MR. WHITFIELD. My time has expired. I recognize Ms. DeGette. MS. DEGETTE. Thank you very much, Mr. Chairman. Dr. Gottesman, I want to ask you some questions that I also talked to Dr. Insel about and the first one is, that--and by the way, I applaud your determination to raise the bar here. I think it is important and I think we would all agree. And the Chairman was also alluding to what I talked to Dr. Insel about which is, we are getting ready to do NIH reauthorization in this committee and Dr. Zerhouni wants more centralized decision-making that would then take the inter- institute cooperation to a higher level which I think is a good idea. But my question is, it seems to me that the physical tracking of these tissue samples, and heaven knows what else that we are keeping at NIH, is at a very rudimentary level, and if we are going to have more cross-institute cooperation, which I think is really the cutting edge of medical research, how on Earth can we hope to achieve those laudable goals if we don't really make a push for much better cataloging and much better cross-referencing? DR. GOTTESMAN. I agree with you, and I think that-- MS. DEGETTE. Well, how can we do it? Do you-- DR. GOTTESMAN. Well, I mean, I have a variety of authorities and I also have ability to persuade people above and beyond my authority. So in terms of tracking samples as the institutional official human subjects' research, I can require that we know that every sample has been approved by an IRB before it gets used, before it gets sent out and so on. In terms of the requirement that there be scientific tracking programs, electronic databases, there I use my persuasive powers to make it clear that these are important scientific as well as management issues for our scientific directors. We hold them responsible. I delegate to them responsibility for tracking human samples, making sure they are properly used, and under that authority, I can ask them to make sure that they know where the samples are. MS. DEGETTE. But do you intend to have some kind of a standard protocol throughout the institutes that other people can access? DR. GOTTESMAN. Well, as I said, the needs of each of the institutes are somewhat different. The type of protocols that are carried on at NIMH and the Cancer Institute are really quite different in kind. MS. DEGETTE. Right, but what I am saying is, if you have a bunch of tissue samples at those two institutes, just cataloging what you have got there and what people are using, that is not different. DR. GOTTESMAN. No. So there is a term in computer networking called interoperability. MS. DEGETTE. Yes, I know that. DR. GOTTESMAN. And if we let 1,000 flowers bloom and we say everybody needs to develop a system for tracking and we don't require that those systems talk to each other, then we have a problem. MS. DEGETTE. Sir, this is exactly what I am saying. DR. GOTTESMAN. The advantage we have at NIH is, we have a central clinical center which is really supported by taps on each of the institutes. That clinical center has a database that I mentioned which includes all the different-- MS. DEGETTE. And how long has that been in place? DR. GOTTESMAN. It is about a little over a year. MS. DEGETTE. So that was not in place when the-- DR. GOTTESMAN. No, no. MS. DEGETTE. Would that system have--right now if something like this happened now, would that system stop it? DR. GOTTESMAN. No, that system doesn't track clinical samples but-- MS. DEGETTE. So what are we going to do to stop it? DR. GOTTESMAN. In order for an investigator to be able to use that system with respect to their clinical samples, it would need to be interoperable so that the fact that we have invested so much in the central system will really force the interoperability of the other systems. They won't be useful to our scientists unless they can interact with the central system. So what I am saying is that-- MS. DEGETTE. Okay. You know, I-- DR. GOTTESMAN. --we are heading in the right direction. MS. DEGETTE. Okay. I may follow up with some more questions because I frankly don't understand what you are saying. I want to talk to you about this chart. I am sure you have seen this, the one that Dr. Insel gave us, and I think it is all swell that we have all of these cross checks and so on, but as I was sitting here looking at this chart, if somebody wanted to take some tissue samples and just go outside the chart around the arrows, there is nothing in here that would prevent that from happening. If someone just wanted to do that--I mean, within the institutes--I think this is great, the IRBs, the board of scientific counselors, the Office of Technology Transfer and so on. If someone just wanted to take those tissue samples out, go to a pharmaceutical company and profit on the side, this system would not have a safeguard. Wouldn't you agree? DR. GOTTESMAN. Yes. So what you are saying is that if somebody--if we say what the rules are and somebody willfully breaks those rules by not reporting-- MS. DEGETTE. Right, which is what happened in this case. DR. GOTTESMAN. Or taking samples and not reporting that they have used them for that purpose. MS. DEGETTE. Right. DR. GOTTESMAN. There is nothing in the current system that would prevent that. MS. DEGETTE. Right. Even in this beefed-up system. DR. GOTTESMAN. And I am hard pressed in any kind of enforcement process to be able to answer how to prevent an individual from doing that except to say that there needs to be some sort of auditing function tied in to all of these processes so that we know maybe not for every person who is involved but on a representative basis how it is that the system is working. MS. DEGETTE. Well, I have two suggestions. Number one is, if you beef up your tissue tracking system which we can talk about more later, then even if somebody is going out beyond that, if they take the issue samples out, you have got some kind of computer model that would say well, where did they go, they didn't go over to another institute or something, that would be a double check. The second--because the evidence is gone. I used to do a lot of criminal work in practicing law, and if somebody went to the evidence vault at the police department and checked the evidence out, then it didn't show up where it was supposed to show up, then you knew there was a problem. That is very simplistic but it is the same type of thing. And the second suggestion I would make is that if there is somebody who is so guilty of such gross malfeasance as in this case, one might want to think about how the personnel rules at the NIH could be modified so they could be fired before 2 years were up, because he is still there even after this happened. I don't know if you want to comment on any of that. DR. GOTTESMAN. Well, the only comment I would make and I know there is confusion about the various appointment authorities at the NIH, civil service versus Commissioned Corps, the Commissioned Corps is a separate authority. It is a uniform service and they run their operations similar to the uniform military code and they make determinations about hiring and firing people and we do not control that at NIH. MS. DEGETTE. And we might want to look at that. My next question is around the informed consent that the people who originally donated these tissues for, and again, Mr. Chairman, I would ask unanimous consent to submit the consent form for the record. And I am sure you have seen this. You might even have it--you are being handed it. Okay. This is the original consent form that was used for Dr. Molchan's study, and it seems to me--I looked it over and it seems to me fairly specific--you were talking earlier about you really need to look at the informed consent and have it be specific and have it be full, and I support that completely. But it looks to me like in this situation, the informed consent was quite specific and quite thorough for the research study that Dr. Molchan was saying she was conducting. Wouldn't you agree with me? DR. GOTTESMAN. Well, in one sense, yes, but let me point out something in the informed consent that perhaps you didn't notice which changes the tone of it. At the end of the first paragraph, "We hope to obtain information on changes in hormones and brain chemicals"--that is very broad-"that occur in Alzheimer's disease and in depression."--my goodness, that is huge-"as well as clues to the mechanism of the action of lithium." It makes it sort of clear that anything goes, and that is why I think an IRB in looking at this currently would just say this is not acceptable--you can't ask somebody to sign off on something like-- MS. DEGETTE. All right. So even though there is a lot in there, it is that phrase that-- DR. GOTTESMAN. It is that phrase. MS. DEGETTE. So it is an interesting dichotomy, isn't it, because on the one hand you want to have an informed consent that is specific exactly to the research study but then on the other hand, what do you do later on if somebody wants to make a secondary use of these tissues? Do you have--and frankly, as Dr. Insel pointed out, with Alzheimer's or many other diseases, it is likely the donor might already be dead. So how are you going to go back--do you think you go back and get a second informed consent or do you think somehow you draft this form so it is both specific enough to deal with this research study but broad enough to let you use the tissues later? DR. GOTTESMAN. Right. So we have two new requirements I think that will clarify that point. The first is that is absolutely essential in writing up a new protocol to specify not only the intent of the protocol, what the study is about, but what will happen with the samples--how they will be stored, how long they will be kept, what will happen if somebody wishes to use them for another purpose, would there be re-consent, would there not be and so on. And the second point has to do with the requirement for IRB review. If the IRB reviews--for example, if these had gone before an IRB for re-review, the IRB would have looked at the original consent. It might have said well, this is so general that maybe patients understood that this was going to happen with their samples but in fact there is an issue over time that suggests that no one could have conceived of the kind of sophisticated analysis that we are doing now 13, 14, 15 years ago and that therefore patients need to be identified. In fact, Dr. Sunderland has patients who he has followed over the years and are still alive and were involved in some of these protocols and maybe they would conclude, although I don't know for sure, that there would be a need for re-consent. They can either say the risk is very small and therefore the new research can move forward, they can waive consent based on the fact that they believe that there is no risk to the patients and the original consent covered the area, or they can request that there be re-consent, and we re-consent patients all the time. MS. DEGETTE. You know, the other thing, and I know it is always on a case-by-case basis, but the subjects of this study, even though that statement was broad, it said this study is researching this. It didn't say anything about and I give consent for future. I mean, it may be what you might want to look at in some cases is having people give specific consent for this study and then developing a secondary consent form that you could have and you can use these tissues for future use. DR. GOTTESMAN. Well, I would be very delighted to continue this discussion with you because these are issues that the NIH is struggling with and the entire research community is struggling with. MS. DEGETTE. Thank you very much, Mr. Chairman. MR. WHITFIELD. Dr. Gottesman, just as a follow-up on this consent, do you really think that most patients care that much about how their samples are going to be utilized? DR. GOTTESMAN. Well, there have been studies done on this issue, and many patients who are participants in clinical research studies, human subjects research studies, are actually enormously altruistic and they believe--they trust the scientists who are working. They want them to be able to use the samples to help them or to help somebody else and I think maybe the majority of people who participate in clinical research feel that way. On the other hand, sometimes they are uninformed about the potential risks to them. If a discovery is made about some aspect of their physiology that could affect their insurability or their employability, those are really important risks that need to be considered and we would like to be able to reassure people that even if they can't think of problems, that we will be thinking about these things and making sure that samples are not used for purposes that could put them at any risk. MR. WHITFIELD. Just a couple of other questions. In your testimony you stated the NIH will accomplish three things. One, you will provide additional guidance to investigations on material transfers; two, you will require that all transfers of samples derived from human subjects must involve putting it in writing; three, the NIH will clarify that in cases involving human transferred material, that there will be review and approval by senior leadership at the relevant institute. Now, is that already being accomplished or do you have a time guideline for this? DR. GOTTESMAN. Right. So because this involves changes in our technology transfer program, I have more direct authority over the human subjects' part because I'm the institutional official. So we are convening a group of administrators and scientists to consider all aspects of material transfer at the NIH, transfer from laboratories as well as clinical samples. I will promise this committee that those aspects that we promise to do will certainly take place, but there may be other changes in our policy as well, and we want to be able to release not piecemeal but altogether the policy on material transfer at the NIH that everybody understands, that everyone adheres to. MR. WHITFIELD. And do you have a general time guideline on that? DR. GOTTESMAN. I think we can probably accomplish this within a couple of months. MR. WHITFIELD. Now, one other question. We have talked a lot about the collaborative research agreements and we talked about the material transfer agreements, and not being familiar with either one of them I would like to just ask you this question. We have on Exhibit #2, there is a material transfer agreement by the National Institutes of Health, the provider is Trey Sunderland, the recipient is Pfizer, which is the case that we have all been focused on, and in paragraph three when it talks about how the research material will be used, it says, "Research to identify and validate protein markers associated with Alzheimer's disease." Now, is that--from your background as a scientist, your experience, is that too broad or is that adequate or-- DR. GOTTESMAN. Well, I think the problem is that this is a material transfer agreement that is not just transferring materials. It is specifying a collaborative agreement. And I think that under normal circumstances if this had been thoroughly reviewed by a technology development coordinator, the conclusion would have been that this is not an appropriate transfer agreement, transfer mechanism that--I always prefer to see CRADAs because, as I told you, the system is very formalized and works well. But it could have been done under a collaborative agreement with a company, but that has to be signed off by the technology people and the senior leadership at the NIH. So the issue here is not whether this is specific or not specific. It is that it is not an appropriate vehicle to transfer the materials. MR. WHITFIELD. Okay. So it is not an appropriate vehicle? DR. GOTTESMAN. I don't believe so, no. MR. WHITFIELD. Well, I will make one other comment, then I will recognize Mr. Stupak here. I want to ask you to do something for us. I would like for you to work with the National Institute of Mental Health to report to us on all of the underlying data that Dr. Sunderland should have on the GPB shipments to Pfizer that would break down by sample in each shipment and the protocol numbers so that we can get a more clear understanding of the specifics of that because in the conversations that we have had with the various people at NIH, we still are a little bit--we are not sure precisely on the specifics of this. In some of the memos I have seen, I know that the National Institute of Mental Health referred to 11 percent here and eight percent here was used and whatever. We would just like to get a more clear understanding of the exact shipments, the protocol numbers and so forth, and how much was utilized as it relates to Pfizer with Dr. Sunderland. DR. GOTTESMAN. Mr. Chairman, we will do the best we can to get the information. As you know, there is an ongoing investigation and we have been generally instructed by counsel to try not to confuse the different investigations, but I certainly would like to get you that information and I will work with the people at NIH and see if we can make that happen. MR. WHITFIELD. And Exhibit 26 may provide some help to you on that as well, so we can give you a copy of that before you go. We will get a copy to you before you go. At this time I recognize Mr. Stupak. MR. STUPAK. Thank you. Dr. Gottesman, how long have you been at NIH? DR. GOTTESMAN. I have been at NIH 31 years. MR. STUPAK. Okay. In this new position as-- DR. GOTTESMAN. In my current position? MR. STUPAK. Yes. DR. GOTTESMAN. Almost 13 years. MR. STUPAK. Thirteen years. Has this issue ever arose before about use of samples and scientists outside? DR. GOTTESMAN. There are a couple different issues. The use of samples for research purposes is a constant area of discussion at the NIH and we are constantly making policy and the policy, as I said to Congresswoman DeGette, is a kind of moving target. MR. STUPAK. Well, it seems like there was policy for handling hazardous materials or samples but not for this here. Why was-- DR. GOTTESMAN. Well, the NIH policy I think is pretty clear and that is dictated by all the requirements for human subjects' research, that if there is a closed protocol and that somebody wants to use a sample, they need to get permission from the IRB to use that sample. There is an oversight responsibility. MR. STUPAK. So here there should have been an IRB and then was it 46 CFR 45, was that--that should have been followed? DR. GOTTESMAN. Right. That is the controlling legislation, yes. MR. STUPAK. And that should have been followed, right? DR. GOTTESMAN. That should have been followed. What was not made clear earlier this morning was that actually some of these protocols are still open. Some of the samples were sent under open protocols and some of them were sent under closed protocols. There were a total of 16 protocols. MR. STUPAK. Right. DR. GOTTESMAN. And 11 of them had been closed prior to the period when the samples were sent. MR. STUPAK. So-- DR. GOTTESMAN. Five of them are still open and undergoing continuous IRB review. MR. STUPAK. Okay. And then the IRB--it is my understanding Dr. Sunderland was head of the IRB, right? DR. GOTTESMAN. At one--during this period he was the chair of the IRB, yes. MR. STUPAK. So who would he get permission from then to-- DR. GOTTESMAN. The original review and approval of the protocols that allowed the samples to be collected were done with an IRB chair who was another person. He was recused-- MR. STUPAK. Well, the original samples, I guess there are no questions there but then they were moved outside for commercial gain, if he is head of the IRB, who would he get his permission from? DR. GOTTESMAN. So in the course of reviewing the human subjects' materials, we found that in some cases Dr. Sunderland did sign off during the continuing review process on protocols in which he was a co-investigator. MR. STUPAK. So he should have received permission or someone sign off-- DR. GOTTESMAN. Someone else should have done that. That was-- MR. STUPAK. With this new flow chart, will that work? I mean, really. I know we had some comments about this. You are talking about this flow chart here, and how does that make--like if I am head of the IRB, where do I go then to get my permission? DR. GOTTESMAN. I mean, this is one of the very basic principles of the conduct of any human affair. If it is your business which is being reviewed, you don't sit as a chairman on the committee that reviews it. MR. STUPAK. So really what it comes down to, it is not this colorful chart. It really comes down to the integrity of the individual? DR. GOTTESMAN. Well, and the institution. I mean, that should not have been allowed. MR. STUPAK. Right. But in order to bypass the safeguards that any institution puts in whether it is NIH or Congress, it still boils down to the individual, whether or not they are going to follow that protocol, whether they are willing to take that risk and what is the benefit to them, almost like a cost-benefit analysis in a way. DR. GOTTESMAN. Well, as I said to Congresswoman DeGette, it is based on trust but at the same point, we can develop oversight mechanisms that reduce the likelihood that any one individual will absolutely violate the rules. MR. STUPAK. Sure. You indicated in your testimony to the Chairman here that there is still ongoing investigation in this matter. Is that true? DR. GOTTESMAN. Yes, that is true. MR. STUPAK. What area is the ongoing investigation still going on? DR. GOTTESMAN. Well, I mean, Dr. Insel mentioned this morning that the AG and the Justice Department have shown some interest in this case and I don't know the state of-- MR. STUPAK. It is nothing else that NIH is doing other than if Justice asks for something-- DR. GOTTESMAN. Well-- MR. STUPAK. --you will provide them with the information? DR. GOTTESMAN. Following a meeting that I had with the counsel for this committee, when I was made aware of what I thought were problems with the human protections issues, I initiated through my own office and through the Office of Human Subjects Research a paper investigation of the various paperwork-- MR. STUPAK. That investigation is done though, right? DR. GOTTESMAN. It is not completed yet but it is in progress and we have already made a report to the Office of Human Research Protections about it. MR. STUPAK. You said you met with House counsel here or committee counsel, I should say, excuse me. So were you part of the team at NIH that put together the information that the committee requested? DR. GOTTESMAN. My involvement was actually minimal. I mean, NIH separates the oversight of the science from the management issues related to disciplining scientists, for example, but I was involved at one step, which was--there was a committee put together to determine whether in fact there was an overlap between the outside activity and the official duty activity. MR. STUPAK. Right. DR. GOTTESMAN. It was a committee of scientists. MR. STUPAK. That is a little different than what I am asking. This committee had a hearing in 2004 on this issue. We followed it up. Myself and Mr. Whitfield, Chairman Barton, Mr. Dingell, signed a letter in June of 2005 asking for certain information. Were you part of the NIH team that helped put together the response? DR. GOTTESMAN. Yes. Actually, our legislative people came to my office and gave me the questions and asked if I could help get some of the information about what was existing NIH policy. The initial questions were about storage of samples, freezer stability, and so on, and what were policies concerning oversight, and we provided information about human subjects and material transfer. MR. STUPAK. And how about the follow-up letter of January 4, 2006, and January 26, 2006, by this committee, were you part of that team that put together those answers? DR. GOTTESMAN. I am not sure what those refer to but-- MR. STUPAK. Is there any question as to whether or not the human tissue samples collected by NIH scientists using government resources are property of the Federal government? DR. GOTTESMAN. There is no question they are property of the-- MR. STUPAK. Under what authority do you make that statement? DR. GOTTESMAN. The legal authority. I think there is probably some place in the legal code--I mean, this is something that every scientist who comes to NIH is told: Every product of your research here belongs to the Federal government. MR. STUPAK. Everyone has testified to that but no one can point us to the authority. DR. GOTTESMAN. I can certainly have our legal people research it and get you an answer to that. MR. STUPAK. Okay. I mean, the issue came up yesterday too. It was asked a couple times. At the NIH, is there a policy regarding data that is over 5 years old? You know, there has been some testimony that Dr. Sunderland indicated that everything was purged and therefore the data wasn't available anymore. DR. GOTTESMAN. So our research integrity policy which has to do with what scientists are expected to do in terms of maintaining their notebooks and their samples and so on states that samples need to be kept for 5 to 7 years. The new requirements from the Office of Research Integrity, which is part of the Department of Health and Human Services, are fully 7 years and we are in the process--and that is a new requirement--we are in the process of aligning our requirement with that requirement. So the department requirement will be retention of materials, data, samples for 7 years. MR. STUPAK. Then what happens to it after that? DR. GOTTESMAN. Then they can be destroyed or--they can't be used for purposes other than the intended purpose, but they can certainly be destroyed. MR. STUPAK. In this case, with the lithium study, was any of that destroyed, any of that data or research information destroyed? DR. GOTTESMAN. I have no idea. I know at some point there was an e-mail which stated that the material had been purged, the information had been purged but I don't know if that actually happened. MR. STUPAK. Let me ask you this question, if I may. The rules at NIH concerning consulting between like NIH and scientists and private industry I am sure have changed since Dr. Sunderland. I am concerned, however, that the abuses of the system from which Dr. Sunderland profited were not only due to lack of regulation but in fact the lack of enforcement of this regulation. How can you assure this committee that there is now an appropriate level of actual enforcement other than this chart? I like the chart but it doesn't do much for us. DR. GOTTESMAN. Right. Well, one of the points I made in my testimony is, it is not sufficient to make policy. You have to be sure that people understand it, understand the reason for it, have support in order to be able to carry out, and know that there are consequences if they don't follow it. And I think that the current environment at NIH is much more sensitive to the need for oversight and management. Some mention was made about the culture of scientists and the culture of administrators. I think one of the things that I have been working on for sure is convincing scientists that management of science is just as important as the conduct of their science. MR. STUPAK. Your deputy ethics counselor, that is in place now? DR. GOTTESMAN. Yes, so what this represents is-- MR. STUPAK. Let me ask you this. I don't mean to interrupt but time is running short. Does this chart, does it apply to the Corps? We have had testimony that you can't do things about Dr. Sunderland because he is part of the Corps. Would this all apply to the Corps also? DR. GOTTESMAN. Yes. Anyone who is in the Corps who works at NIH is subject to all the same rules and regulations. MR. STUPAK. So if I violate whether I am in the Corps or whether I am at NIMH but not part of the Corps, if I violate one of these rules I could be terminated, I don't need the Corps permission then? DR. GOTTESMAN. No. The problem is that if you are appointed in the Corps, the Corps makes the determination about whether you can be terminated. MR. STUPAK. But yet this so-called accountability chart, if you will, or whatever you want to call it, your chart here, this is going to apply to the Corps? DR. GOTTESMAN. The requirements for people who work at the NIH are the same whether they are appointed-- MR. STUPAK. Corps or civil service or independent-- DR. GOTTESMAN. The decision about hiring and firing is made by the Corps, not by the NIH. That is the issue. MR. STUPAK. I just want to make sure the Corps is going to accept this. DR. GOTTESMAN. They do and they will. MR. STUPAK. Okay. Thank you, Mr. Chairman. MR. WHITFIELD. One other question, Dr. Gottesman. In response to Mr. Stupak, you talked about human tissue samples can be destroyed after 5 to 7 years. Is that mandatory or is that just-- DR. GOTTESMAN. No. I guess it is an expectation that materials--we don't expect them to be retained for more than 7 years. In many cases for the clinical samples that obviously continue to be valuable samples, they should be maintained and I think it an interesting issue. Most of our scientists will continue to keep them, hoard them in their freezers and hoping that they will be useful at some future time. MR. WHITFIELD. Yes, because you can freeze these fluid samples for I guess forever, right? DR. GOTTESMAN. Well, the issue about actually what the lifetime is of these samples in the freezer is a scientific question and I think has not been resolved, at least to my satisfaction. MR. WHITFIELD. It depends on what you are going to use them for and so forth. Okay. Dr. Gottesman, thank you very much for your testimony. We appreciate your being here today and we look forward to working with you as we move forward to maintain the integrity and the sterling reputation of NIH. Thank you. This hearing is adjourned. [Whereupon, at 12:55 p.m., the subcommittee was adjourned.] RESPONSE FOR THE RECORD OF THOMAS R. INSEL, M.D., DIRECTOR, NATIONAL INSTITUTE OF MENTAL HEALTH, NATIONAL INSTITUTES OF HEALTH, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES <GRAPHICS NOT AVAILABLE IN TIFF FORMAT> RESPONSE FOR THE RECORD OF WILLIAM FITZSIMMONS, EXECUTIVE OFFICER, NATIONAL INSTITUTE OF MENTAL HEALTH,, NATIONAL INSTITUTES OF HEALTH, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES <GRAPHICS NOT AVAILABLE IN TIFF FORMAT> RESPONSE FOR THE RECORD OF MICHAEL M. GOTTESMAN, M.D., DEPUTY DIRECTOR FOR INTRAMURAL RESEARCH, NATIONAL INSTITUTES OF HEALTH, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES <GRAPHICS NOT AVAILABLE IN TIFF FORMAT> RESPONSE FOR THE RECORD OF DAVID L. FRIEDMAN, PH.D. The Honorable Bart Stupak Question(s) for David Friedman, Ph. D. Formerly with Pfizer, Inc. June 13, 2006 Subcommittee on Oversight and Investigations Hearing entitled: "Human Tissue Samples: NIH Research Policies and Practices" 1. In his report to an NIMH internal review board, Dr. Sunderland characterized the three-way collaboration involving NIMH, Pfizer, and Oxford Glyocsciences, which yielded no data or publications for NIMH, as unsuccessful. Would you agree with this assessment? No. I thought it went quite well in a scientific sense. 2. If the collaboration did indeed produce significant findings, why would Dr. Sunderland characterize it as a failure? Would he have any reason to think this was the case? I noticed that you transitioned from "unsuccessful collaboration" in (1) to a question of failure to produce significant findings in (2). I think the jury is still out on the general utility of these markers as they traverse the validation process. Pfizer continues to update the patent application periodically, perhaps with new and meaningful marker data. That data should be more visible when the patent issues. Perhaps Dr Sunderland felt it was a failure because nothing got published. Perhaps someone should look into that. 3. Did it strike you as odd that Dr. Sunderland did not want to be mentioned in publicity associated with the collaboration involving OGS? Not really, it wasn't exactly clear why, but not of a scientific concern. 4. Did Dr. Sunderland ever mention why he did not want to be listed? Would there be any reason for a researched interested in publication, and involved in a good-faith collaboration, to not wish to be listed in publicity of this kind? Not clear to me why. 5. How regularly did Dr. Sunderland visit your lab or OGS while you were in charge of the "unknown biomarkers" research? First of all, I wasn't "in charge" of the research as you suggest above. I was the scientific leader, albeit with several layers of management above me also on the team (e.g., Michael Silber, Steve Williams). In terms of the regularity of visits, at least quarterly at Pfizer, with perhaps one or two additional visits per year for special "data-driven" events. Eiseman, E. and Castillo, J., Handbook of Human Tissue Sources, RAND Monograph Report, 7 (1999). See also U.S. Congress, Office of Technology Assessment, New Developments in Biotechnology: Ownership of Human Tissues and Cells - Special Report, OTA-BA-337 (March 1987) at 3. Hakimian, R. and Korn, D., "Ownership and Use of Tissue Specimens for Research," Journal of the American Medical Association, November 24, 2004, at 2500. Eiseman, E. and Castillo, J., Handbook of Human Tissue Sources, RAND Monograph Report,xvii (1999). Id. The National Bioethics Advisory Commission (NBAC) estimated that as of 1998, more than 282 million specimens of human biological materials were stored in the United States, accumulating at a rate of more than 20 million cases per year. Hindin, T., "Technology and Clinical Trials," Applied Clinical Trials, April 2006 at 12. Mills, J.F., "Precedents for Good Storage Practice," Applied Clinical Trials, April 2006 at 58. Email on "Harmonization and Repositories," from Lana R. Skirboll, Ph.D., Director, Office of Science Policy, NIH, October 27, 2005 to various NIH staff. Id. The current total number of tissue samples at the NIH is unknown. As the NIH wrote to the Committee in a letter dated August 15, 2005: "NIH does not maintain a central listing of all tissue samples in its possession. Each laboratory is responsible for storing and tracking all samples within its possession. NIH requires that each investigator obtaining such samples complete a Human Pathogen Registration Document, [ ], which requires information on the principal investigator, the location of the work, the agent or human blood, body fluid or tissue being worked with, and the names of all individuals working with the particular material being registered. The document does not require the investigator to supply the number of samples that he/she plans to work with or obtain. NIH currently has 390 Human Pathogen Registration Documents on file for human blood, body fluids, and/or tissues. Currently, 663 laboratories maintain human blood, body fluids, and/or tissue samples. [footnote omitted]. A total of 2340 employees are registered for work involving human blood, body fluids, and/or tissues. It is important to note that these numbers apply only to active research protocols. In addition, NIH maintains biorepositories to provide investigators with pathological samples for research uses. Two are maintained by the National Cancer Institute, . . . " Committee staff requested numerous times to interview Dr. Sunderland, but through his attorneys he declined to be interviewed. The consulting payments were in addition to sums Pfizer paid Sunderland for speeches or discussions with potential prescribers of Aricept and the occasional advisory board participation. Those payments added an additional $311,000 over roughly the same period of time as the consulting agreements. While such payments are now not permitted under the ethics rules, a special NIH ethics panel concluded that had Dr. Sunderland requested approval for these speeches, they would have been approved under the standards that predated the Committee's investigation and resulting reforms. In an attached response to an e-mail dated May 12, 2006, from NIH staff to Committee staff, NIH stated: "Where have tissue samples sitting in a freezer that have been collected from patients in an intramural trial, whom do these samples belong to? Still belong to the donor? NIH? Lab scientist? Government? If it does not belong to the government, want explanation of why not. Tissue samples collected within the intramural program belong to the Federal Government." Committee understands from NIH that the NIH has recently made a referral to the OIG-HHS on this issue of undisclosed patent applications. As discussed later, Ms. Conn believed that the next step in the process was Pfizer sending her a copy of the MTA to review. This matter is discussed in more detail later in the report. According to Pfizer records, what remains of the samples represents about half of what was shipped by Dr. Sunderland. Pfizer is "happy to work with NIH to arrange the return of the samples." June 6, 2006 e-mail from Daniel Kracov, Esq. (outside counsel to Pfizer) to Committee staff. December 8, 2004, letter from Robert F. Muse, Esq. to Holli Beckerman Jaffe, Director, NIH Ethics Office, page 7. Id. , page 8. Title 45 Code of Federal Regulations, Part 46. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: ethical principles for the protection of human subjects of research. Washington, D.C.:Government Printing Office, April 18, 1979. U.S. Department of Health and Human Services publication GPO 887-809. Position Statement, The Ethics and Humanities Subcommittee of the American Academy of Neurology, Neurology 1998, 50: 592-595. That silence or ambiguity would not have been unusual for most clinical research protocols because there had been no requirement to address future uses. It was not until January 2006 that the NIH Office of Human Subjects Research (OHSR) explicitly addressed this issue, revised its guidance, and issued "Sheet 14 Guidance on the Research Use of Stored Samples or Data." In that guidance, researchers are required to submit a written protocol to an NIH IRB that includes a description of how samples will be tracked, how samples will be stored to be protected from loss or destruction, plans for samples at the conclusion of the protocol, and what circumstances would cause the lead researcher to report a loss or destruction of samples to the IRB. In discussion with Committee staff, the NIH Deputy Director of Intramural Research, whose office includes OHSR, stated that this revision occurred in response to the Committee's investigation. David B. Resnik, J.D., Ph.D., National Institute of Environmental Health Sciences (NIEHS) Bioethics Bulletin, "Human Research Q&A," Spring 2005, at 2: Question: "I have access to some leftover tissue samples from another investigator's work. I would like to conduct some research on these samples. Is this research on a human subject? Do I need to submit a protocol to the NIEHS's Institutional Review Board (IRB)? Short answer: This is not research on a human subject but you still need to contact the IRB before using these samples in research, since the samples were taken from human subjects." After several months of inquiries by Dr. Molchan, Dr. Sunderland sent 0.5 cc paired spinal-fluid samples from eight Alzheimer's disease patients and two elderly normal volunteers to an outside researcher. In his interview with Committee staff, the Director of NIMH raised the issue of whether this transfer was in compliance with NIH guidelines along the same lines that questions had been raised by Dr. Sunderland's transfer of samples to Pfizer. Dr. Molchan, however, told the Committee staff that the research purpose of the outside researcher was the same purpose (to conduct a lithium study) in the study she had not been able to complete. Letter dated May 10, 2006, from Daniel A. Kracov, Esq., Arnold & Porter (on behalf of Pfizer, Inc.) to Committee staff. The NIH recently advised the Committee staff that the internal NIH investigation on human subject research issues had identified 16 different studies connected to Dr. Sunderland's transfer of human samples to Pfizer. For example, in 2005 Dr. Robert Cohen took over as the Principal Investigator for Dr. Sunderland in a few of the protocols involved as sources of spinal fluid for Pfizer. May 10, 2006, letter from Daniel Kracov, Esq. to Committee staff: "In April 1998, what was Pfizer's understanding of Dr. Sunderland's authority to sign an MTA? In 1998, Pfizer sought to confirm Trey Sunderland's authority to enter into the MTA on behalf of NIH. In this regard, Pfizer's Kathy Smith was referred to Kathy Conn at NIH [the NIMH Director for Technology Transfer] who, to Kathy Smith's recollection, confirmed that Dr. Sunderland was authorized to execute the agreement. It has been Pfizer's standard practice when dealing with academic institutions, including institutions such as NIH, not to accept an investigator's claim to have authority to sign an agreement without consulting with an appropriate representative of the contracting institution." E-mail from Kathryn E. Monaghan [Smith] to Trey Sunderland, March 24, 1998: "Trey, I spoke with Kathy Conn today and she also reconfirmed that we can proceed with the MTA immediately and work out the CRADA vs. Consult part in due course. I fedexed various forms of the MTA on Friday -- hope you got them yesterday?" Exhibit 31. E-mail from Gemma Flamberg (NIH) to Alan Slobodin (Committee staff), June 1, 2006. (Exhibit 37) Pfizer, however, did not actually receive any serum from NIMH (March 31, 2006, letter from Daniel A. Kracov, Esq. to Committee staff). (Exhibit 38) T. Sunderland, "Prospective search for Alzheimer's disease (AD) biomarkers," in Downing, ed., Biomarkers and Surrogate Endpoints: clinical research and applications, Proceedings of the NIH- FDA Conference held on 15-16 April 1999 in Bethesda, Maryland, USA, at 39, 40 (Elsevier, 2000). Dr. Sunderland also highlighted this collaboration in a paper he prepared for a 2000 NIMH of Board of Scientific Counselors review of research in his branch.