ࡱ> ^`] @ ?bjbj00 "`RbRb7R\6$R4#f||||WWW"""""""$ $Rr&x"5WW55"||"$www5j||"w5"ww `!|Z B&Y!""H4#a!,&&!T6!&!Wgw)pWWW""RR aRR Conduct of Emergency Research FDA Public Hearing, Oct 11, 2006 Michelle H. Biros, MD, MS Professor of Emergency Medicine Department of Emergency medicine Hennepin County Medical Center and University of Minnesota 701 park Avenue South Minneapolis, Minnesota 55415 612-873-5683 FAX; 612 -904-4241  HYPERLINK "mailto:Michelle.Biros@gmail.com" Michelle.Biros@gmail.com Affiliation; Society for Academic Emergency Medicine Introduction The Society for Academic Emergency Medicine ( SAEM ) is grateful for the opportunity to provide comments from its membership to the FDA related to The Exception from Informed Consent (EFIC) in Emergency Research Circumstances. The Coalition of Acute Resuscitation Researchers (the Coalition) joins SAEM in this presentation, and we include comments from members of the American Academy of Emergency Medicine (AAEM). In 1994, SAEM took the lead in discussions related to issues of consent in emergency research circumstances. The Coalition was developed at the request of SAEM to broaden these discussions and included thought leaders from throughout the research community. The Coalition developed a Consensus Document that was subsequently endorsed by over 25 professional organizations concerned with emergency research, and presented concepts that were eventually incorporated into the FDAs Final Rule ( 21CFR 50.24 ). Since the codification of the Final Rule into Federal Regulations in 1996, SAEM has continued to discuss the implementation of the Rule, educate it members on use of the Rule, and monitor the use of the Final Rule within the emergency research community. In May, 2005, the Societys journal, Academic Emergency Medicine, sponsored a consensus conference entitled: The Ethical Conduct of Resuscitation Research; Exception from Informed Consent. The proceedings of the conference were published in the November 2005 issue of AEM and widely disseminated. This issue of the journal also includes original research on the application, interpretation and attitudes related to the Final Rule. With this background in mind, we feel well qualified to offer these comments related to the 2006 FDA Guidance document, and to address specific issues raised by the FDA, and to offer additional questions of our own. In doing so, we must recognize that the 2006 Guidance document is fashioned around the Final Rule as it currently exists. We strongly believe that a better approach would be to revisit the Final Rule itself, and use existing experience and data to determine whether and where it is meeting its goals, and where its requirements have missed the mark. The FDA has asked us to consider many questions but time does not allow us to address them all. Instead;w, we will briefly mention a few three general areas to provide focused thoughts related to the issue of EFIC . Comments on the FDAs questions on; In terms of the Scientific aspects/ ethics, #4 . The FDA has asked if there are challenges that have not been explicitly addressed in the regulations in designing scientifically rigorous and ethically sound emergency research and, if so, if these challenges should be addressed now. We believe there are many challenges that have not yet been addressed by the regulations. Some relate to specific patient populations that are not considered in the Final Rule, such as children. Yet, in the decade since the Final Rule was implemented, our society and the emergent illnesses and injuries we face have changed. Children are now as likely as adults to be victims of life- threatening or high morbidity events, such as gunshot wounds, terrorist attacks, illicit drug overdoses or emerging infectious diseases . Children also suffer from life threatening illnesses or injures that are rarely seen in adults, and which have been poorly studied. Restricting pediatric resuscitation research to only those circumstances for which consent can be obtained would limit the research questions we can ask, narrow the methodologies we could apply , and bias the results we would obtain. It is also erroneous to assume that all children who present with emergencies will be accompanied by parents or guardians who can provide informed consent. Many of these children are brought to hospitals unaccompanied and many have parents or guardians who are far too distraught to be approached for informed consent within a narrow therapeutic window. To deny children the possibility of direct benefit though participation in resuscitation research contradicts the FDAs mandate to include children in research, and, frankly, is unethical. We believe that better guidance on the application of EFIC or a reconsideration of the Rules requirements in order to address issues in emergency research in children is paramount. Resuscitation research also includes studies of varying complexity , across a wide spectrum of pathologies. As medical care advances and new knowledge is developed, the risks and benefits of particular interventions should change.. Previously highly fatal events may become critical high morbidity events instead. It is an ethical and moral medical imperative to not only save lives, but to improve the quality of life. While the Final Rule allows for research in high morbidity events, these may be very difficult to predict or to define as the clinical spectrum changes. One set of regulations is not appropriate for all studies and we believe that the concept of incremental risk assessment should be considered. Other challenges relate to the changes in the research environment itself, and the Final Rule currently offers no room for growth, for unanticipated developments, or for change based on experience and data regarding use of the Rule. For example, the Institute of Medicines recent report on the Future of Emergency Care describes a paucity of clinical effectiveness trials for the treatment of critically ill or injured patients in the out of hospital setting. We have a growing cadre of EMS research expertise and some studies using the Final Rule have been completed in the out of hospital setting. Yet we have data that suggests fulfilling the requirements of the Final Rule in the out of hospital setting is inconsistent even within the same EMS service. We must ask the EMS research community what unique challenges they have encountered and determine if the regulations address these unique aspects of out of hospital research. Should the same set of regulations apply to all clinical environments that who have unique challenges and patient populations served? The translational emphasis of the NIH has led to the development of at least three emergency based research networks ( PECARN, Neuro-NETT, and ROC sponsored respectively by MCHB, NINDS, and NHLBI). All aim to test new treatments for critical illness or injury. Many studies undertaken by these networks will require research using EFIC. Challenges are always present when trying to successfully and consistently implement a protocol at several sites and we need to determine the unique challenges related to EFIC. For instance, there are variable levels of comfort and experience among IRBs regarding the use of EFIC. The Final Rule vests increased responsibilities and authority into IRBs . The details are complex and to date, IRBs have been given limited guidance and little feedback. Is it reasonable to expect that all IRBs will achieve a working knowledge of this complex and infrequently used Rule? How can we ensure a consistent and fair protocol review at all sites? Some IRBs either refuse or are reluctant to allow research using the EFIC ,which results in a demographic bias in study enrollment. Should a central IRB be established for network studies ? What are the practical and ethical implications of a central IRB and how should it be formed? These are tough questions with very significant ethical implications. These are just a few of the many challenges that were never anticipated when we wrote the Final Rule , and now is the time to address them. Failure to do so is scientifically worrisome and ethically dangerous. Additional human subjects protection The FDA has asked a series of questions regarding community consultation as a patient safeguard While the concept of community consultation is attractive and in theory allows community values to be factored into the research process, the reality is that community consultation has been consistently problematic. We have essentially no evidence to show that it is effective, and in fact, much evidence to suggest otherwise. In the decade since the Final Rule was established, less than a dozen studies examining the methodology of community consultation have been undertaken and published. These studies have documented the ambiguity inherent in conducting community consultation and the lack of appropriate evaluation methods to assess the adequacy of the process. The goal of community consultation is to elicit the opinion of the community related to a research protocol, and to use the information obtained to deliberate on any concerns before the study is implemented. In order to provide useful discussion, the community should understand the protocols under consideration. Data from the Public Access Defibrillation trial suggest that even members of focus groups with multiple educational sessions, do not generally understand the actual study goals and protocol. The Final Rule asks for community consultation but does not require a measure of its effectiveness. How, then, do we make sure the community understands? To our knowledge there is no formal reporting of how community consultation has altered protocols using EFIC and very little information about how IRBs utilize the information provided. If we do not measure the effectiveness of our community consultation efforts, how do we know if we have indeed protected patients at all? We suspect that the methods used to achieve community consultation have not resulted in broad representation of the community of potential subjects or the community in which the research is to be conducted. Studies that which have documented this process have shown that few people attend public meetings and those who do are likely to be non-representative of the at risk community being studied. For example, we conducted a study of a drug to sedate acutely agitated delirious cocaine intoxicated patients. Despite great effort, we could not recruit a single cocaine addict to participate in community consultation. Who then in the community is providing feedback and does it reflect the true concerns of the targeted study population? How do we know that we have heard their potential concerns , since we do not measured this? If community understanding is lacking, and involvement is non -representative, the goals of community consultation are not met and it becomes a cumbersome and futile exercise. Given a decade of experience with the Rule, we must revisit the actual intent of community consultation and determine if this purpose is still meaningful We do not believe it will ever be possible to determine if community consultation provides adequate patient safeguards against research risks since there are no measures of its effectiveness and no possible way to quantify it. Therefore ,instead of asking if CC provides adequate patient safeguards, the better question is, How can we better protect patients? Public notification and disclosure are other safeguards built into the Final Rule. Disclosure of a full research protocol or certain scientific information to the public may cause concerns similar to those outlined above. However, the intent is different.; it is a disclosure and not a discussion. If we include protocols or specific scientific information in the public notification, how can we be sure the public understands ? the information or the protocol? If no assessment of understanding is included , has the purpose of the notification been met? Does the public really need to know all of these details? Even more basic, can we be sure that these measuresthis information actually reaches the public, as the process was intended? ? We are not required to measure this according to the current regulations. As an example, we interviewed patients in ED waiting rooms in three large cities after a very aggressive and widespread public notification campaign had been conducted regarding the existence of a study using EFIC . Less than 5 % of individuals surveyed at any of the sites actually knew of the study. Conclusion The balance between meaningful individual patient protection and the potential societal benefit of conducting research without consent is essential and part of our key values as emergency researchers and practitioners. Whether this is achieved by the Final Rule in a patient protective manner remains unknown. We appreciate the FDAs willingness to listen to our comments and hope this information will prove useful to the FDA and assist in reducing some of the existing barriers to resuscitation research. However, we appeal to the FDA to seriously reassess the Final Rule itself, in light of our concerns that it has not effectively and meaningfully provided the safeguards for vulnerable patients as intended. Just as it is our medical responsibility to constantly expand our knowledge and treatment strategies and to learn from our research, we also believe it is our responsibility to reassess the ethics and the rules by which research is conducted. In conclusion, SAEM, its concurring partners, and the Coalition of Resuscitation Researchers request that the FDA convene a meeting of stakeholders, similar to what occurred 10 years ago, and revisit the requirements of the Rule for conducting research without consent in special emergency circumstances. The goal of this process should be to inquire broadly about the experiences of implementing the Rule to date, and to factor in that experience into a Rule of the future. Thought leaders must be brought together to discuss how to better meet the needs of our vulnerable patients within an evolving research environment. 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