News

Changes at U Penn Health System

William N. Kelley, MD, who served as the dean of the Univer-sity of Pennsylvania Medical School and CEO of its Health System for more than a decade, was relieved of these administra-tive duties in mid-February. The decision to change leadership was announced by University Presi-dent Judith Rodin and was com-plemented by the announcement of Dr. Peter G. Traber's ascendance to interim dean and CEO. Traber, 44, had been the chairman of the department of medicine. Dr. Kelley, however, will remain a “distinguished member of the fac-ulty,” according to a news release put out by the university.

The decision did not come as a surprise to those who have fol-lowed the drama of Penn's re-cently troubled health system. Re-ports from the Philadelphia Inquirer estimate a loss of almost $300 million over the past two years. The University's bond rating was downgraded last March, de-spite the system's seeming turn-around after cutting 20% (approxi-mately 2800 employees) of its work force and a $16.7 million net in-come in the first five months of fiscal year 2000.

The troubles besieging Penn re-flect the changing climate for aca-demic health centers across the country [the recent breakup of the UCSF-Stanford merger was re-ported in the March JIM]. Faced with increasing competition and an emphasis on the financial bot-tom line, Penn, with Kelley as the architect, had spent years en-gaged in an aggressive campaign of expansion. At the core of this expansion was the plan to in-crease Penn's share of the mar-ket through sheer physical size, buying three area hospitals and a network of more than 250 phy-sicians.

Although he was committed to increasing the size of the U Penn health system (and consequently, the number and breadth of ser-vices it provided), Kelley was also a great proponent of research. The school's rankings in terms of out-side support rose steadily from his assumption of power in 1989, cat-apulting the institution into the upper echelons of academic med-icine. NIH support reports list the medical school at number 2 for 1999 and 1998, and one has to go back to 1994 to find a ranking below the top 5 (the school was number 6 that year).

News from NIH…

The following first appeared on the NIH Office of Extramural Research website on April 7:

“Beginning with applications submitted for the January 2001 Council round (generally, those applications submitted for the June/July 2000 receipt dates), IRB approval is not required prior to NIH peer review of an application. As part of the peer review process, the peer review group carefully considers whether the application includes the necessary safeguards to protect the rights and welfare of research participants.

This change in policy is intended to provide flexibility at the institutional level. The institution may still determine that certain lines of research (e.g., scientifically or ethically controversial research) or mechanisms of research (e.g., multicenter clinical trials) should receive IRB review prior to submission of the application.”

For the complete text of the revision and rules pertaining to it, go to: www.grants.nih.gov/grants/irb_review_pol.htm

Action in Washington Surrounding Allegations of Fetal Tissue for Sale

In 1993, when the congressional ban on federally funded research on fetal tissue transplants was lifted, de-riving a profit from procuring such tissue was made a felony. Such a measure was enacted to prevent the potential for exploitation by unscru-pulous providers of tissue, and was seen as a necessary safeguard to pre-vent a black market-style traffic in tissue and to remove the possibility of coercion of prospective donors. “Reasonable” fees are supposed to cover costs incurred from obtaining the tissue, transporting it, and storing it. In November of last year, Repre-sentative Tom Tancredo (R-CO) came forward with allegations that at least one company was engaging in fetal tissue profiteering, and the House resolved to hold a committee hearing in the second half of the leg-islative session.

This March, the day after ABC's news magazine 20/20 aired a report alleging fetal tissue profiteering by a company called Opening Lines, the House Commerce Committee's Sub-committee on Health and Environ-ment held a hearing. Caught on hid-den camera was Dr. Miles Jones, a pathologist and owner of Opening Lines, bragging that he was turning a good profit trafficking parts: “If you have a guy that's desperate for a heart, then he'll pay you whatever you ask.” Jones was also quoted as describing how to talk a client into donating. “You can do something that's got all the legal mumbo-jumbo in it and they'll sign it any-way. If you have someone trained to ask properly you can get 80, 90 percent consent rates.” Jones, who was subpoenaed to appear and pro-vide testimony on March 9, is being held in contempt of Congress for skipping the hearing.

Events took a turn for the bizarre, however, when Lawrence Dean Al-berty, Jr., the 'star witness' of the proceedings recanted earlier testi-mony. Alberty, a former employee of Jones, stated that his charges of ille-gal practices, which were made on a video produced by Life Dynamics, Inc., a nonprofit antiabortion group (who paid Alberty $10,000), were “what they wanted to hear.” Alber-ty's prepared statement before the subcommittee ranged from the graphic to the cryptic, describing in detail the effects that watching late-term abortions had on him and re-counting his move to join an anti-abortion group. He later proclaimed “I only want the American public to understand that I'm not against re-search, not against the right for a woman to choose which path she may take but to let the American people stand up and have the truth. The truth is not evil, not hate, not punishing and not the dark tunnel.”

With Alberty's credibility in doubt and Jones absent, much of the focus shifted from allegations of wrongdoing to pleas from research and patient advocates against allow-ing outrage about this incident to halt fetal tissue research. Indeed, the ma-jority of those testifying at the hear-ing were there to urge caution in the wake of the allegations. Prepared statements were read by Dr. Hannah C. Kinney, a pediatric neuropatholo-gist at the Children's Hospital in Bos-ton; Dr. Samuel Cohen, chairman of the Department of Pathology and Mi-crobiology at University of Nebraska Medical Center; and Joan I. Samuel-son, President of the Parkinson's Ac-tion Network.

Dr. Cohen seemed to articulate the concerns of the research and advo-cacy communities, who feared an end-run style backlash engineered by antiabortion advocates seeking to ex-trapolate from the Jones' incident: “I believe that the great majority of those who use fetal tissue in their research are scrupulous in following the letter and the spirit of the law, among other reasons because they are aware of the great sensitivity around its use.”

Representative Tom Coburn (R-OK), a family physician, has re-sponded to all of this by introducing a bill called the “Human Fetal Tissue Reporting and Disclosure Act of 2000.” The bill is designed to amend the Public Health Service Act and would require researchers to file a disclosure statement with the Secre-tary of Health and Human Services. Specifically, the bill calls for a dis-closure statement that contains: “(1) a list (including the names, addresses, and telephone numbers) of each en-tity that has obtained possession of the human fetal tissue involved prior to its possession by the filing entity, including any entity used solely to transport the fetal tissue and the tracking number used to identify the packaging of such tissue; (2) a de-scription of the use that is to be made of the fetal tissue involved by the filing entity and the end user (if known); (3) a verification that the fetal tissue was obtained with the le-gal consent of the donor of the tissue; (4) a description of the type of fetal tissue involved, including a determi-nation of whether the tissue was ob-tained from an induced abortion; (5) a description of the quantity of fetal tissue involved; (6) a description of the amount of money, all fees, or any other object or other considerations of value, that is transferred as a result of the transference of the fetal tissue involved, including any fees received to transport such fetal tissue to the end user; including the amount of such fee; and (7) any other informa-tion determined appropriate by the Secretary.”

Also included in the bill are pro-visions that would maintain the con-fidentiality of those involved in the harvesting of fetal tissue, the donor's identity, and any other information that could be used to identify individ-uals or “entities” disclosing informa-tion.

Additional Comings & Goings

IOM Committee to Gather Information on IRBs and Data Privacy Protection

The Institute of Medicine (IOM) held a workshop in March to out-line its new project concerning health services research data pri-vacy protection and institutional re-view boards (IRBs). Sponsored by the Agency for Healthcare Re-search and the Office of Assistant Secretary for Planning and Evalua-tion, the project is a response to “public interest and concern over the privacy of personally identifi-able health information” and will consist, in part, of collecting data over the course of the next 10 months about “various practices and policies regarding data privacy protection.”

In 1996, the Health Insurance Portability and Accountability Act (HIPAA) was enacted by Congress. Included in the Act was a directive that charged the Secretary of Health and Human Services (HHS) with devising guidelines concerning pri-vacy of personally identifiable health information (PHI). Such in-formation is not explicitly protected by federal law, which can lead to disclosure of PHI without the pa-tient's consent or even knowledge. The Secretary's recommendations were presented in September 1997, and when Congress failed to meet an August 1999 deadline for the enactment of privacy legislation, HHS published a proposed regula-tion (NPRM) that would establish “standards for privacy of individu-ally identifiable health informa-tion.” This NPRM is currently un-der review and could be finalized by HHS sometime this year. The IOM reports in its project scope, however, that “the Secretary's rec-ommendations and most of the pri-vacy bills introduced in the 105th Congress would permit research us-ing PHI without the person's ex-plicit permission if the research project were approved by an insti-tutional review board.”

Indeed, the proposed HHS reg-ulation goes so far as to add four new criteria to those already in ex-istence under the Common Rule (a rule adopted by over 17 federal agencies that lays out federal policy for the protection of human subjects from research risks). These sugges-tions allow for use of PHI without individual authorization when “the research would be impracticable to conduct” without such data; when “the research project is of sufficient importance to outweigh the intru-sion into the privacy of the individ-ual”; when “there is an adequate plan to protect the identifiers from improper use and disclosure”; and when “there is an adequate plan to destroy the identifiers at the earliest opportunity consistent with the con-duct of the research justification for retaining the identifiers.” Critics have noted that the suggestions as listed by the Secretary would require IRBs to step out of their traditional roles of judging the safety and soundness of a project and ask them to make judgment calls on a project's 'sufficient importance.'

On a less sweeping scale, the IOM's project seeks “to gather information on the current prac-tices and principles followed by IRBs to safeguard the confiden-tiality of PHI used for health ser-vices research purposes, in par-ticular, to identify those IRB practices that are superior in pro-tecting the privacy, confidential-ity, and security of PHI.” Like-wise, the committee, officially known as the Committee on the Role of Institutional Review Boards in Health Services Re-search Data and Privacy Protec-tion, wants to collect information “on the current practices and principles employed in privately funded health services research centers (that are not typically subject to IRB approval)” and “if appropriate, recommend a set of best practices for safeguarding the confidentiality of PHI that might be voluntarily applied to health services research projects by IRBs and private sponsors.” The study and its findings are scheduled to be made public on August 1.

NIH and FDA Seek to Increase Oversight of Gene Therapy Research

In early March, the Food and Drug Administration (FDA) and National Institutes of Health (NIH) announced two new initiatives designed to insure greater agency oversight of gene therapy clinical trials and increased protection for those patients partici-pating in trials. The joint effort comes just a month after the Senate Subcommittee on Public Health and Safety hearing, during which admin-istrators from both agencies were questioned about the effectiveness of their respective mechanisms for over-sight of research.

Since September 17, when an 18-year-old trial participant, Jesse Gels-inger, died after undergoing gene therapy at the University of Pennsyl-vania's Institute for Human Gene Therapy, the issues of oversight and safety have taken center stage. News of Gelsinger's death reverberated far beyond the clinical research commu-nity, garnering attention in Congress and mobilizing some patient advo-cate groups who feared a backlash moratorium on all gene therapy re-search would spring from the inci-dent.

What made the case so unusual is that the young man was not sick be-fore his death. Previous patient fatal-ities in gene therapy trials had been attributed to the life-threatening dis-eases present in the subjects. Gels-inger, however, suffered from a mild form of ornithine transcarbamylase (OTC) deficiency, a genetic disorder that impairs an individual's ability to process dietary protein. Left un-treated, OTC can lead to ammonia buildup, causing coma and eventu-ally death, but Gelsinger's condition was kept under control through a reg-imen of drugs and diet.

Penn's voluntary halting of the study and disclosure of the patient's death proved a watershed event. In the wake of Penn's disclosure, some 652 adverse events were reported to NIH by researchers around the coun-try, dwarfing the number, 39, that had been previously submitted. Pub-lic interest in the matter seemed to grow over the next few months as accounts of researchers under-report-ing adverse events and agency per-sonnel inadequately following up on information in their possession sur-faced. Since January, FDA has closed down all gene therapy research pro-grams at Penn, citing regulations vi-olations. More recently, research was halted at Tufts University School of Medicine for reasons the FDA has not yet disclosed.

Perhaps the greatest revelation of the intervening months, though, was not in the realm of gene therapy trials but in defining the almost byzantine relationships between the various federal agencies charged with moni-toring the research. The Recombinant DNA Advisory Committee (RAC), which reports to the director of NIH, is charged with reviewing all gene therapy protocols to insure compli-ance with NIH guidelines. There is no authority implicit in this role, only the responsibility to review and pub-licly discuss experiments. In turn, NIH has authority to enforce its guidelines at any federally funded fa-cility or private facility where federal funds are used to support research. Again, the mandate is there to hold public discussion of experiments. FDA, as a regulatory body, is respon-sible for providing final approval for the new drug used in a gene therapy trial, and so researchers are required by law to report adverse events to FDA as well as NIH. Reports sent to FDA, however, must be kept confi-dential in order to safeguard potential proprietary information.

OPEN IN VIEWER

AFMR Executive Director Michele Sumilas and Senator Bill Frist, MD, (R-TN), Chair of the Sen-ate Subcommittee on Public Health and Safety.

That FDA appeared to be receiv-ing timely reports of adverse events while NIH was not caused concern on two fronts. First, why weren't the records of NIH and FDA identical if researchers are required to report to both? And second, if FDA had re-ports of adverse events, why wasn't action taken? Questions like these were among those asked at the Feb-ruary Senate hearing chaired by Bill Frist (R-TN). Frist's opening state-ments seemed to set the tone of the meeting, which was one of concern that gene therapy be recognized for its tremendous potential but that the agencies charged with oversight and the researchers conducting investiga-tions operate according to both the letter and the spirit of the law. “It is my hope that by a discussion and examination of the events that have unfolded since last September, we can learn from previous mistakes and move forward in the field of gene therapy.

Acknowledging that “monitoring by study sponsors of several recent gene therapy trials has been less than adequate,” the FDA and NIH will institute the Gene Therapy Clinical Trial Monitoring Plan, one of the two initiatives designed to “complement and advance current patient protec-tions.” The second, the Gene Trans-fer Safety Symposia, is designed to “enhance the conduct of gene therapy trials by convening a conference of investigators at which the appropriate monitoring practices will be dis-cussed by the most experienced pro-fessionals in the field.” The safety symposia will be held on a quarterly basis; both initiatives began immedi-ately upon their announcement in March, with the first symposium tak-ing place the week the announcement was made at the RAC meeting in Bethesda, Maryland.

As part of the new plan, sponsors of gene therapy will have to provide monitors to “verify that the rights and well-being of human subjects are protected; that the conduct of the trial is in accordance with the protocol, regulatory requirements, and good clinical practices; and that data re-porting (including safety reporting to IRB, FDA, and NIH) is accurate and complete.” Researchers will also be required to submit their monitoring plans to FDA in advance, and FDA will conduct “for cause” site visits to assess institutional compliance with regulations governing gene therapy research.

An important part of this joint initiative is the emphasis on coop-erative action between the two agencies. Among these are NIH's plan to conduct “not for cause” site visits “to review institutional un-derstanding of, and compliance with” NIH guidelines. Attention is also being paid to public disclosure of information, and FDA “plans to issue a proposed rule on the public discourse of information regarding gene therapy clinical trials that would provide more information on these trials to the general public.” [See sidebar for the list of individ-ual and cooperative actions the agencies have taken or will take “to bolster the protection of study par-ticipants and the integrity of gene therapy trials.”]