(Circulation. 2000;101:e9052.)
© 2000 American Heart Association, Inc.
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Shaking the World of Gene Therapy
In a move that shook the nascent world of gene therapy, the University of Pennsylvania announced on May 24, 2000 that it was ending clinical trials of gene therapy in its Institute for Human Gene Therapy and that it will redirect its efforts at the molecular, cellular, and animal model level.
The Institute, which is led by gene therapy pioneer James Wilson, MD, had initiated many pioneering clinical trials in the past and was considered a world leader in the field. However, in the wake of the September 17, 1999 death of 18-year-old Jesse Gelsinger, a participant in the phase I clinical trial to treat an inherited disorder called ornithine transcarbamylase deficiency, the actions and procedures of the institute came under increasing scrutiny, both from within the University and from federal agencies. Although no clinical trials will be undertaken at the gene therapy institute, the University said that trials might be undertaken elsewhere in the greater institution.
Dr Wilson released a statement that was quoted in the Washington Post (May 25, 2000:1). In it, he indicated that the Institute would "refocus our efforts in the preclinical area—with the goal of developing a foundation of science necessary to ensure the ultimate success of this field. Although numerous scientific obstacles exist, gene therapy has tremendous potential to omeday prevent or cure life-threatening diseases."
The University’s president, Judith Rodin, took action after receiving the results of an investigation by an independent review panel. The panel, which was led by William H. Danforth, MD, chancellor emeritus and vice chair of the board of trustees at Washington University in St. Louis, was charged with developing an understanding of the operations of the gene therapy institute, particularly concentrating on how it handled clinical trials.
Other action planned by Penn officials include the following:
- Assessing all clinical trials to determine the level of monitoring
necessary for strict compliance with all applicable regulations.
- Initiating a comprehensive review of ethical decision-making specific to all research using humans, and creating an Institution Review Board (IRB) with special expertise in evaluating gene therapy.
- Conducting a formal comprehensive review of the IRB system to strengthen its abilities to protect the vital interests of patients by building on significant changes in IRB policies and procedures already in place.
- Reviewing policies and procedures on conflict-of-interest specific to both perceived and actual conflicts, including those inherent in the investment and funding of provocative medical therapies.
- Initiating a comprehensive review of ethical decision-making specific to all research using humans, and creating an Institution Review Board (IRB) with special expertise in evaluating gene therapy.
The Danforth Committee noted that all clinical trials with human subjects are likely to be under stricter scrutiny in the future from the public, federal agencies, and individual institutions. In April, the American Society of Gene Therapy proposed new guidelines that would prohibit all investigators and team members who are directly involved in patient selection, informed consent, and management of a clinical trial from having equity, stock, or comparable holdings in the company that is sponsoring the trial.
The day before the University of Pennsylvania announcement, Health and Human Services Secretary Donna E. Shalala announced federal initiatives to improve the oversight of clinical research and, in particular, that which involves the transfer of genetic material. According to Shalala, "In the last few years, we’ve seen dramatic advances in the effort to find new therapies for cancer and other diseases, and we’ve taken new steps to protect the safety of patients in clinical trials. But the explosion in biomedical research has also brought new challenges, as more researchers are becoming involved in commercial ventures. Today’s actions are designed to further strengthen government oversight of all biomedical research, including gene transfer research, and to reinforce institutions’ and researchers’ responsibilities to follow internationally accepted ethical standards and federal guidelines."
The most controversial part of the federal plan involves the institution of civil monetary penalties for individuals and institutions who violate rules concerning informed consent of patients and other research practices. The penalties would total as much as $250 000 per clinical investigator and $1 million per institution. Currently, the US Food and Drug Administration can only issue warning letters or impose sanctions that halt research until problems can be fixed. Shalala and her advisors believe that the financial penalties will give the federal agency better tools to halt researchers and institutions who refuse to follow federal guidelines. Congress will have to pass legislation to allow the new fines before they can be imposed.
The federal government also plans to institute the following:
- An aggressive educational and training effort aimed at clinical
investigators, IRB members, and associated personnel.
- Special guidance on informed consent, clarifying the requirement that institutions and sponsors audit records for evidence of compliance with informed consent. Risky or complex trials will require special measures, including third-party observation of the informed consent process.
- Requirements for improved monitoring of small-scale early phase clinical trials by investigators. Large phase III trials will be required to have Data and Safety Monitoring Boards.
- New guidance on conflict of interest rules that will apply to all research funded by the National Institutes of Health.
- Special guidance on informed consent, clarifying the requirement that institutions and sponsors audit records for evidence of compliance with informed consent. Risky or complex trials will require special measures, including third-party observation of the informed consent process.
Shalala told reporters that she planned to write the presidents of the nation’s research institutions to warn them that the entire university will be held at fault when rules about patient safety are broken.
"We must ensure that patients are well protected and properly informed when they choose to enroll in a clinical trial," said Jane E. Henney, MD, Commissioner of the Food and Drug Agency. "By maintaining high standards and requiring that all investigators adhere to them, we can be sure that the nation’s biomedical research enterprise will continue to earn the trust of research subjects."
Media Drug Stories Misleading
Newspapers and television broadcasts misrepresent the value and risks of new medications and often fail to report how much such drugs cost, according to a study in the June 1 issue of the New England Journal of Medicine (2000;342:1645-1650).
The study also showed that no more than 40% of news stories disclosed potential conflicts of interests between authors and companies funding the studies. "Major scientific journals require study authors to disclose industry links, as evidence suggests that commercial funding of research may lead to more favorable research outcomes," said Ray Moynihan, the lead author of the study and a medical journalist with the Sydney-based Australian Financial Review. He said news media should adopt the same standards.
The study also faulted news articles for lacking statistical analyses of the benefits of a potential drug, for publishing only relative benefits of the new medication, for failing to disclose the hazards of medication, and for failing to determine whether a drug was cost-effective.
"The media are a very important source of public health information," said Stephen Soumerai, MD, a coauthor of the study and a Harvard University School of Medicine professor of ambulatory care and prevention. "But stories on new drugs can be misleading when they fail to address potential conflicts of interest and don’t discuss both relative and absolute benefits, risks, and costs. We hope this study provides some focus for journalists and editors who are continually striving for greater accuracy in medical coverage."
California Court Says Managed Care Plans Can’t Drop Doctors Without Cause
In May, the California Supreme Court ruled that Metropolitan Life Insurance Company had violated California’s common-law right of fair procedure when it dropped the late Louis E. Potvin, MD, from a preferred provider panel. The court said when an insurer has a large share of a market, it must give physicians a reason for dropping them and a hearing.
According to American Medical News (June 5, 2000:1), the ruling effectively voids the clauses in provider contracts that allow physicians to be terminated without cause—at least in California. Although the California Medical Association called the ruling a victory, the case has been remanded to a lower court for trial. At that trial, lawyers for the estate of Dr Potvin will have to prove that the MetLife decision made a substantial impact on the physician’s practice.
Although many attorneys told American Medical News that this case will be cited in similar cases around the nation, it remains unclear what effect the ruling will have in other states.
Take Another Aspirin
If stroke patients receive an aspirin as soon as they arrive at the hospital, they may not suffer recurrent incidents during the high-risk time, according to researchers from Oxford University in England (Stroke. 2000;31:1240-1249). "Early aspirin therapy should be used much more widely," said the study’s lead author Zheng Ming Chen, MD, DPhil. "The message is: If someone comes to the hospital with acute ischemic stroke, start aspirin therapy as soon as possible and continue it long-term."
Dr Chen and his coauthors examined information from 2 stroke trials,
the Chinese Acute Stroke Trial (CAST) and the International Stroke
Trial (IST). Each trial included 20 000 patients. Their
analysis showed that the risk of recurrent ischemic
stroke was reduced by one-third after just a few weeks of aspirin
therapy. The overall absolute benefit in preventing further stroke or
death is estimated at 
9 per 1000 people per month.
The study included patients who arrived at the hospital within 48 hours of the onset of symptoms. In the CAST study, half of the patients were given 160 mg of aspirin per day for 4 weeks. Half of those in the IST study received 300 mg of aspirin per day for 2 weeks.
Aspirin has not been given immediately to stroke patients because of fears that it would cause bleeding in the brain. However, Dr Chen said this study shows that the benefits of aspirin outweigh the risks. When 773 patients who had a bleeding stroke were evaluated, the researchers found that their outcomes were not significantly different from similar patients who did not receive aspirin.
Guidelines from the American Heart Association for treating acute ischemic stroke (Circulation. 1996;94:1167-1174) indicate that although aspirin might be effective in treating patients with an acute stroke, it should not necessarily be used with clot-busting thrombolytic therapy.
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