Recent Developments/Initiatives to Protect Patients in Gene Therapy Research

Managing the Risks of Human Gene Therapy Research
by Ellen F. Wodika, MA, MM, Senior Risk Advisor, CNA HealthPro
and June E. Leigh, RN, MS, ARM, Director, Risk Management Services, CNA HealthPro

The recent death of Jesse Gelsinger, an 18-year-old participant in a research trial at the University of Pennsylvania Institute for Human Gene Therapy, is the first known fatality related to clinical gene therapy research. Gelsinger’s death triggered Congressional hearings, articles in prominent journals and general controversy regarding protocols for protecting research subjects. This document will review the facts of the case, recent developments/initiatives from the FDA/NIH regarding gene therapy research, and risk management implications. This article examines the Gelsinger case as well as the wider questions raised by the case about managing the risks associated with human gene therapy research.

Background Facts
Human gene therapy involves the infusion of healthy genes to correct serious medical conditions. The healthy gene is attached to a vector, often a virus -- that becomes the conduit to the genetic source of the illness. Researchers strip the virus of potentially harmful genes while leaving intact its ability to insert itself into the genetic material of targeted cells. One of the major goals of human gene therapy is to produce safe, effective vectors that can penetrate target cells and enable the implanted genes to express their proteins, without causing infections or other side effects.¹

Jesse Gelsinger had a rare, inherited liver disease that was being treated under a clinical trial in the Institute for Human Gene Therapy’s research program. However, he was not in the terminal stage of the disease, a standard criterion for patients enrolled in a gene therapy trial. Gelsinger’s vector was a common respiratory tract virus, known as adenovirus. Following an infusion of corrective genes, Gelsinger became critically ill, as the adenovirus vector apparently triggered an immune reaction in Gelsinger’s lungs. These led to complications, including single-lobe ARDS (Adult Respiratory Distress Syndrome), that ultimately proved fatal.

Prior to Gelsinger’s death in 1999, approximately 4,000 people had participated in over 350 human gene therapy trials.²

The Gelsinger case raises many questions, including the following:

• Should children (who will not directly benefit from the findings) be involved in initial research to test the vector’s toxicity, or should researchers proceed to test the vector on adults without the toxicity data?
• Is there a greater degree of risk associated with injecting the adenovirus vector directly into a hepatic artery, in order to control the flow of the vector directly into the liver, rather than a peripheral vein?
• Did researchers ignore evidence indicating that adenovirus triggers an immune response at certain levels?
• Did pressure to produce an effective vector influence the researchers’ methods?
• Did researchers follow the adverse events reporting procedures required by the Food and Drug Administration (FDA), National Institutes of Health (NIH) and the Recombinant DNA Advisory Committee (RAC)?
• Was the informed consent process sufficiently clear and thorough?
• Are conventional patient protection safeguards applicable to gene therapy clinical trials?

Following their investigation of the Gelsinger case, the FDA and the NIH launched two major regulatory initiatives: the Gene Therapy Clinical Trial Monitoring Plan and the Gene Transfer Safety Symposia.

The first initiative requires sponsors of gene therapy trials to routinely submit their quality monitoring plans to the FDA, which will review them on a continuing basis to identify areas of potential improvement. The initiative allows onsite "for cause" inspections of clinical trials to ensure compliance with clinical trial plans and to determine if monitoring is sufficient to identify and correct deficiencies.

The initiative also requires sponsors of gene therapy trials to assess the experience and training of test monitors. Monitors must report back to the sponsor regarding the following subjects:

• protection of subjects’ rights
• compliance with research protocols
• adherence to regulatory requirements
• observance of quality clinical practices (www.ifpma.org/pdfifpma/e6.pdf)
• thoroughness and accuracy of data and safety reporting

Findings must be reported to the Institutional Review Board (IRB), the FDA and the NIH, even when an independent data and safety monitoring board is in place.

The second major initiative involves sponsoring quarterly symposia of scientific and medical experts, who will meet to share information and discuss data on gene transfer research. Topics of discussion will include (among others) safety data monitoring, good clinical research practices, and criteria and informed consent practices for gene therapy research participants. The FDA and NIH will also help support educational programs sponsored by academic and professional organizations. Both agencies will continue to participate in satellite training broadcasts, RAC meetings and education programs hosted by such associations as the American Society of Gene Therapy and the American Industrial Hygiene Association.

The FDA and the NIH also plan a series of additional efforts to promote patient safety:

• The FDA now requires clinical trial sponsors to provide the agency with more quality control information about cell banks and other products with potential use in gene therapy research.
• The NIH will perform "not for cause" site visits at NIH-funded institutions to review their understanding and compliance with NIH guidelines on gene transfer research.
• The NIH requires all institutions that conduct gene therapy research to review their policies and procedures for conformity with NIH guidelines and to revise them accordingly.
• Investigators of gene therapy trials must report all serious adverse events (SAEs), including those from inactive trials, to the NIH. The FDA will also onotify the NIH of receipt of SAE reports and changes to gene transfer protocols.
• An NIH task force will review the agency’s oversight role in gene therapy clinical trials.
• The RAC has established a subcommittee to review SAE reporting, analysis and public disclosure.
• The FDA plans closer oversight of "Investigational New Drug" applications in gene therapy research.
• The NIH is developing an interactive web-based database for public access to gene transfer research data.
• The FDA announced its intention of publishing a new rule governing public disclosure of information on gene therapy clinical trials.
• The FDA requires that all clinical trials be listed with the Library of Medicine, allowing patients access to information about past trials and adverse effects of experimental medicine.
• The FDA is asking for progress reports on clinical trials earlier in the process.
• The FDA and the NIH require that patients be fully informed about procedures before giving their consent to treatment.
• The RAC has emulated FDA reporting requirements by requiring researchers to report immediately unexpected SAEs or SAEs that may have been caused by experimental therapy.
• The NIH requires investigators to provide the agency with a description of the education program completed by key personnel (i.e., those responsible for the design and conduct of the study) in the research project.
• The NIH is requiring investigators to submit monitoring plans for Phase I and II research trials to both the NIH and to the IRB.
• The NIH announced plans to publish additional guidelines regarding disclosure of potential conflicts of interest in clinical research.
• The NIH has developed its own online research training program, which can be downloaded and adapted by other research institutions. The program, "Protection of Human Research Subjects: Computer-Based Training for Researchers," can be accessed at the NIH web site at http://ohsr.od.nih.gov/cbt.

At the same time, the Health and Human Services (HHS) Office for Protection from Research Risks (OPRR) has launched certain patient protection initiatives of its own:

• The NIH, the FDA and the OPRR will develop educational standards and training requirements for researchers, clinical investigators and IRB members.
• The informed consent process will include audits of clinical trial participants’ medical records by research institutions and sponsors to ensure compliance with federal guidelines, and informed consent documents will be reviewed whenever unexpected events occur during the clinical trials. Consumers, industry representatives and other interested parties will have the opportunity to help oversee the informed consent process.
• Legislation will be introduced into Congress calling for monetary penalties of up to $250,000 for researchers who fail to comply with federal regulations, and up to $1 million for institutions.

Risk Management Implications
Frequently, risk management programs work backwards by identifying after the fact what could have been done to avoid an untoward event. The Gelsinger case underscores the importance of several safety priorities in human gene therapy research. These issues are reviewed in the "Damage Control" section. In addition, the case raises certain issues that can best be addressed in light of risk management planning. These are described in the "Proactive Management" section.

Damage Control
The concept of damage control demands that we identify the most severe potential events. It is then possible to conduct a root cause analysis that examines every process, decision and event that affected the outcome. At each step in the analysis, the following questions should be answered:

• What are we doing at this stage to avert the untoward outcome? (prevention)
• How do we know the specified action is actually being done? (documentation)
• Who is responsible at this stage? (accountability)

Zero tolerance. Zero-tolerance for human death is the ethical standard expected in human gene therapy research. We see this ethic at work in many different arenas where human life is at stake. In the overwhelming majority of cases, the potential benefits of research are not considered worth the death of a single individual. Research programs are halted whenever a human death occurs.

Despite our best efforts, however, there is always the potential for death in research that includes human subjects. Minimizing this risk requires thorough planning, stringent safeguards and enforceable research protocols that demonstrate the researchers’ efforts to prevent death. The research protocols should include a selection process with strict inclusion and exclusion criteria for patient participation. In addition, it is critical that subjects be told during the informed consent process that there is some risk, however slight, of death due to participation in the study.

Informed consent. Following the death of Jesse Gelsinger, some members of his family commented on the inadequacy of the information that they received during the informed consent process. To reduce the risk of such allegations, it is essential, first of all, that the information included in the patient informed consent process be accurate and complete, and that the patient’s understanding of the information be thoroughly documented. Second, the informed consent form must clearly state whether the research is intended to study safety or to assess the agent or treatment. Third, the information provided should fully disclose known morbidity and mortality data and risks.

When necessary, the informed consent process should address the particular concerns of parents of minors who are being considered as subjects. These concerns include, but are not limited to, the long-term implications of participating in the study and whether participation may preclude some treatment options in the future.

Compliance with external reporting requirements. The third issue that attracted significant negative publicity to the researchers and the University of Pennsylvania was the degree of compliance with federal reporting requirements for reporting serious adverse events. The protocols must include written procedures for identifying and reporting SAE's and documenting compliance with reporting procedures.

It is critical that:

• the lead researchers and all the research team members agree on what constitutes an SAE
• SAE's will be reported according to required protocols
• one individual be responsible for overseeing and filing required

Compliance with IRB requirements and quality control. Strict compliance with the host IRB’s requirements is imperative on the part of research sponsors and investigators. The IRB requirements should specifically address criteria and procedures for SAE reports. Research sponsors and investigators should also provide the IRB with information regarding the maintenance of ethical and safety standards throughout the study. The IRB is responsible for monitoring reporting procedures, changes in experimental protocols, the conduct of investigators and the adequacy of information provided by sponsors to the investigators.

Conflict of interest. Another pressing issue is the potential impact of financial considerations and conflict of interest disclosure on research trials. Financial support for human gene research should be clearly stated, and investigators and institutions should distance themselves from financial gain linked to research results. Research institutions should have clearly defined policies to prevent the appearance of conflict of interest, and should present these policies during the orientation process and require investigators to complete a conflict of interest questionnaire before beginning the trial.

To encourage further discussion about conflict of interest in human research trials, the HHS, NIH, FDA and the Centers for Disease Control and Prevention sponsored a conference on the topic of "Human Subject Protection and Financial Conflict of Interest" in August 2000. In addition, the May 2000 journal of the American Society for Gene Therapy issued a policy statement on financial conflict of interest in gene therapy and clinical research trials. The statement emphasizes that patients’ interests are primary and must be carefully protected, and that research studies should be conducted by investigators in a safe and objective manner without conflicts of interest.

Proactive Management
The efforts described above are recommended to reduce the risk of potential disasters and to limit the damage that such disasters can cause. Additional risk management activities should focus upon improving the quality of the research, heightening trust and recognizing excellence by the scientific community. The near-term goal is to promote human gene therapy research at the research institution, in the larger scientific, community, and among legislators and the public. Long-term objectives include increased funding and stronger public and political support for human gene therapy research, based on the medical breakthroughs that such research have produced and will continue to produce.

To assure a bright future for gene therapy research, it is necessary to educate people about the benefits of human gene research. People are often frightened by or hostile to ideas that they do not fully understand. Educating people about these complex issues can help minimize this fear. Educational events are most effective if led by working investigators and tailored to the particular audience’s level of knowledge, i.e., a program aimed at the entire hospital community should differ from one directed at volunteer and auxiliary groups. Information about gene therapy research can also be communicated through newsletters to hospital employees and friends of the hospital, and by arranging interviews with local newspapers and broadcasting stations.

By regularly disseminating general information about its human gene therapy research program, an institution can demonstrate to the public and to politicians that it is operating in good faith and that it is committed to candor, openness and safety.

For additional information on the Gelsinger case, see the following Web sites:

• www.upenn.edu,the independent review panel report on the University of Pennsylvania Institute for Human Gene Therapy (IHGT)
• www.med.upenn.edu,the IHGT response to the FDA