Contemporary Issues for Protecting Patients in Cancer Research Workshop Summary (2014) / Chapter Skim
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Contemporary Issues for Protecting Patients in Cancer Research: Workshop Summary
Contemporary Issues for Protecting Patients in Cancer Research: Workshop Summary
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There are also long-standing concerns about the processes and forms used to obtain informed consent from patients participating in clinical studies. These changes and challenges raise new ethical and practical questions for the oversight of clinical studies, 1 Defined as a health care system in which science, informatics, incentives, and culture are aligned for continuous improvement and innovation, with best practices seamlessly e mbedded in the care process, patients and families active participants in all elements, and new knowledge captured as an integral by-product of the care experience (IOM, 2013)
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This workshop,3 held in Washington, DC, on February 24 and 25, 2014, brought together clinical researchers, government officials, members of Institutional Review Boards (IRBs) , and patient advocates to discuss a wide range of topics, including • The current regulatory arena and challenges in protecting partici pants in cancer research • The patient perspective on current protections for research participants • New oversight challenges stemming from genetic advances and the use of biospecimens in cancer research • The evolving context of cancer research and care within LHCSs and multisite trials • Education and research needs related to improving participant protections in research This report is a summary of the workshop.
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Minimal risk studies, such as quality of life studies using questionnaires, can undergo what is known as expedited review, which entails review by the IRB chair or by one or more experienced IRB members designated by the chair, rather than review by the full IRB membership.4 Some studies, such as those involving the study of existing publicly available data or specimens, are considered so low risk that they are exempt from IRB review.5 Common Rule and HIPAA Regulations governing IRBs for oversight of human research came into effect in 1981 and were further defined by the 1991 Common Rule,6 which specifies a baseline standard of ethics and protections of human research participants that has been adopted by 18 U.S. government agencies that support research.
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• ely less on informed consent for uses of data in an LHCS R that are considered routine, and instead pursue other models of patient engagement to enhance protections for research participants. • rovide educational opportunities to enhance the health and P scientific literacy of the public.
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• evelop and evaluate models of the consent process. D • evelop and disseminate evidence-based best practices for D informed consent and incorporate feedback loops to foster improvement.
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, said that under HIPAA, health care operations include "conducting quality assessment and improvement activities, including outcomes evaluation and development of clinical guidelines, provided that obtaining generalizable knowledge is not the primary purpose of any studies resulting from such activities." Health care operations also include "population-based activities related to improving health or reducing health care costs and protocol development." Research, in contrast, is defined by both HIPAA and the Common Rule as a "systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge." Authorization to use or disclose PHI must specify in writing how, why, and to whom the health information can be used or disclosed. This authorization is distinct from, and in addition to, the traditional and wellestablished informed consent for research specified in the Common Rule.
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Perfection is often the enemy of the excellent." Deborah Collyar, founder and president, Patient Advocates in Research was particularly critical of what she called an evolution of patient consent from a document aimed mainly at protecting patients to one aimed at protecting institutions and thus viewing patients as liabilities. "We have to stop saying that informed consents are for patients and then create them for the institutions that are managing risks.
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. The Privacy Rule offers two ethods to deidentify personal health information.
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in which health data stripped of the 18 identifiers specified by the Privacy Rule is subjected to both a risk estimation and risk mitigation procedure (Benitez et al., 2010; Malin et al., 2011; Xia et al., 2013)
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Names; 2. ll geographical subdivisions smaller than a state, includ A ing street address, city, county, precinct, ZIP code, and their equivalent geocodes, except for the initial three digits of a ZIP code, if according to the current publicly available data from the Bureau of the Census: (a)
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One study he conducted reviewed all actual reidentification attempts through 2010 and found only one case with health data subjected to deidentification of the 18 required identifiers -- a reidentification success likelihood of 0.00013 (El Emam et al., 2011)
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FIGURE 1 A risk-based deidentification model. Health data stripped of the 18 identifiers specified by the HIPAA Privacy Rule are subjected to both a risk estimation and risk mitigation procedure.
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Leiter agreed but noted that some clinicians are still not 100 percent sure that such investigations are not systematic research. As such, they tend to err on the side of caution and either forgo the investigation or seek patient consent and IRB review of it.
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Regulations and incentives should ideally be aligned to encourage the most ethical conduct. Speaking in regard to the oversight of patient consent and authorization, Jeffrey Botkin, associate vice president for research integrity at the University of Utah, and chair of the Secretary's Advisory Committee on Human Research Protections, stressed that "Incentives are too strong in favor of greater complexity [of consent forms]
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audit found that the median page number for the consent forms used in 97 NCI-sponsored Phase III cancer clinical trials was 16, reported Mary McCabe, chair of the Ethics Committee and director of the Survivorship Program at Memorial Sloan Kettering Cancer Center. Leiter pointed out that patient authorization forms tend to either be so short and understandable that they are too general and do not provide meaningful protections, "or they are incredibly meaningful because they explain absolutely everything, but then you get the 22-page, 10-point font
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Recognizing the shortcomings of consent forms, NCI started an initiative in 2011 to write an improved informed consent template that was first used in NCI-sponsored clinical trials in 2013. The new template has several changes over the older template provided by the Institute, including • Use of a study title that a lay person can understand.
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. He strongly suggested shortening and simplifying consent forms, noting that the people reading them "are physically and emotionally not at their best." Cleveland suggested using health lexicons to simplify the language used in consent documents and determining their reading levels by using the tools offered by various word processing programs.
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Informed Consent Process Several speakers noted that the consent form is only one component of informed consent, and that the consent process is equally if not more important. Botkin pointed out that the current consent process does not usually ascertain whether participants understand key information elements before a decision is made.
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" Any misinformation should be corrected until potential research subjects indicate that they have understood by correctly answering all the questions. Medical professionals need to make clear that the need to repeat information is due to their failure to clearly convey the information rather than the "fault" of the potential subject.
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We have to address them as such," Cleveland said. She noted that "the sickest people tend to be the most vulnerable," and make privacy of their health information a low priority compared to using it to find a cure for their disease.
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Such support would include reassuring patients that their doctor will continue to see them, that they will have support to address side effects, and that if they are not doing well on the study, their care will be reevaluated and a new care plan drawn up. Although several speakers made suggestions for improving both consent forms and the consent process, Botkin noted that which ones might work best is unknown because insufficient research has been done to address this question.
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. Consent Tools Several participants suggested that a number of new technologies could improve the consent process, including interactive computer programs and audiovisuals that educate the patient about the trial; tablets that patients can use to fill out forms in the waiting room; and greater involvement of
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In the example he showed, a cartoon version of a person appears on the computer screen and talks about how consent forms can be long and complicated "and my job is to help you understand as much as possible." The conversational agent then asks the patient questions, such as if they have ever been in a research study before, and responds with empathy when needed. For example, if the patient says their previous experience with a research study was bad, the agent responds, "I'm sorry to hear that.
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As McCabe said, "There is a whole new landscape out there and we really ought to move beyond that paper consent form and thinking about it in the usual way." Beyond Consent Leiter pointed out that although informed consent is important, it alone cannot ensure adequate protection of participants in clinical
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"There are lots of other ways besides consent to layer on protection and lots of different tools to employ, and they too often get ignored in policy and legal discussions about data protection." HITECH The Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009 called for numerous changes to the Privacy Rule, and in 2013, HHS announced a number of changes to the Rule and guidance (HHS, 2013)
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information is going to be used for it," Bianchi said. "It has removed some of the roadblocks to researchers, but it is not clear how far it is going to get us," she added, noting that it is not yet clear if current ongoing studies can be grandfathered because they described potential future research in the informed consent process.
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and never to discriminate inappropriately. Data Quality and Integrity: Persons and entities should take reasonable steps to ensure that individually identifiable health information is complete, accurate, and up-to-date to the extent necessary for the person's or entity's intended purposes and has not been altered or destroyed in an unauthorized manner.
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It might have a chilling effect on the ability to learn from and conduct important types of innovation." Taylor said that other proposed changes would aim to better calibrate IRB review to the level of risk. For example, one suggestion was to revise and simplify the review approach for expedited review by eliminating the requirement for continuing review.
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This was in response to the recognition that multiple IRB reviews fail to improve human subject research protections, while lengthening the time of review and diverting valuable resources. The ANPRM also called for improving consent forms and the consent process.
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Clayton noted that 88 percent of patients surveyed at Vanderbilt about sharing their deidentified health data were either neutral or stated that data sharing made them more amenable to participating in research. A similar percentage of patients in Group Health Cooperative reconsented to data sharing.
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subjects," she said. Leiter noted the increasing willingness of the younger generation to share personal information, including health information, on Internet forums, but noted a "fundamental lack of knowledge as to how unprotected those data are." Health data uploaded onto the Internet have no legal protections, she said.
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By providing participants with easy access to information about clinical trials that are investigating treatment alternatives, PEER is doing the case management that is included in the HIPAA definition of "health care operations" that enables use or disclosure of protected health information. PEER affords individual participants a level of privacy protection that is beyond HIPAA, according to Terry, because it holds no personal information other than that which the participant or their representative explicitly provides, or requests that a third party provide, and the participant maintains continuous control over the use of his or her information.
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A number of access con trols on PEER enable participants to specify, in a granular manner, medical researchers, organizations, data analysis platforms, and others that can and cannot use their health information and for what purpose. These controls, which can be operated independently of each other, include: • Discovery, which controls who can discover their information • ontact information, which determines who can access their C contact information • xport, which controls who can export deidentified informa E tion from PEER Participants have the option to edit their responses to these controls from a computer or smartphone, as well as to indicate if they want more information about a specific study or organization before deciding how it can use their health data.
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Usual core components of registries include: functionality for data entry, apolicy reflecting the goal of PEER being participant-centric Privacy and access database of deidentified data, and facility for inquiry and/ or analysis of that data based on the privacy and access policy of the registry owner, to which all participants must consent in advance. Contact information for individual participants -- if available -- is most often loosely coupled, and outside the registry.
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Workshop participants reported a wide range of perspectives on all these issues. Patient Consent for Use of Archived Biospecimens Researchers are increasingly using archived biospecimens, such as blood and tumor tissues, and related health data in genetic studies that could have
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This response to the low risk of reidentification of genetic information pays more attention to creating systems of oversight and control, instead of just saying we are going to do informed consent." Peppercorn added that requiring reconsent for use of biospecimens for future unanticipated studies would violate the trust of the participants who donated those biospecimens with the anticipation that they would help advance science and help future patients. "This issue of public trust that we worry about, in terms of violating informed consent, really cuts both ways.
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Peppercorn and his colleagues weighed several factors in determining the appropriateness of sharing genetics data from the biospecimens without undergoing the expensive and likely unfeasible process of reconsenting the patients. These factors included whether there were • Potential societal benefit from sharing data; • Informed consent for future research; • Uncertainty of risks from future unspecified research explained in the consent form; and • Data sharing consistent with the goals and terms of the initial consent form, even though the language used was not perfect by modern standards.
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Peppercorn concluded his presentation by noting, "We are not going to be able to predict the questions we are going to want to ask in the future or what the technologies will be." Consequently, he said that the informed consent process is going to be imperfect for future research and thus should be accompanied by "a transparent and multidisciplinary process that our participants would be happy with for reviewing the use of their archived biospecimens and deciding what we can or can't do with them." He also suggested prospectively improving informed consent for future unspecified research. Such consents should be broad, given the broad scope of science, and should explain the uncertainty of what that future research will be.
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• Maintain health information privacy and a patient's right to not know. Return of research results could also incur prohibitive costs on research teams, biobanks, and the health care system in general, as well as potentially have negative impacts on research progress, Bradbury said.
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• Recognize that research and clinical care are often intertwined to the benefit of both, especially in the cancer arena. Bradbury noted that "Oncology providers are often thinking about research as part of that armamentarium that we discuss with our patients and patients are often coming in looking for trials." Clinically Actionable Findings According to Bradbury, currently most researchers and ethicists find it acceptable to not return research findings to individual patients unless there appears to be a consensus that select results are clearly actionable clinically, could change the course of clinical care for a patient, and have been confirmed in a CLIA-certified laboratory.
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Bradbury, Clayton, and Jarvik noted there appears to be general agreement in the field that consent forms should address the return of individual results to participants who are currently enrolling in research studies, and that researchers have no duty to hunt for actionable genetic findings beyond the aims of their research. This perspective was advanced in a recent report, Anticipate and Communicate: Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-to-Consumer Context, by the Presidential Commission for the Study of Bioethical Issues (2013)
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Another conferee pointed out that even if the treating physician may know how to interpret the genetic data, they may be poorly trained in how to manage an issue that could affect other family members. Jarvik concurred, noting that "the education of general physicians is woefully inadequate" with regard to interpreting genetic findings.
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" The HIPAA Privacy Rule is silent on whether authorization is required from the personal representative or next of kin of deceased individuals to conduct research using their personal health information. Some organizations interpret the Privacy Rule to require researchers to obtain authorization from next of kin or a waiver of authorization from an IRB or Privacy Board to access the personal health information of those research participants who have died (Ness, 2007)
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This learning derives from clinical trials of previously untested treatments; studies of surgical, procedural, or other innovations in treatments currently given; quality improvement studies; and comparative effectiveness studies. Another category of study that is increasingly being used is called the pragmatic trial, which is aimed at discovering whether an intervention is effective under real-world
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Faden pointed out that the main two types of knowledge generated by a learning health care system are focused on improving patient safety; quality improvement, and determining which existing clinical options work best for patients (that is, comparative effectiveness research)
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She added that "the learning health care system confronts the fact that the way in which we attempt to generate new knowledge now, while incredibly important and successful at giving us all kinds of wonderful new treatments and advances in health care, has, in many respects, failed us in not being able to give us as much information as quickly as we need it in order to make really good decisions in everyday experience of being a patient or a doctor." But Faden added, "It is not known yet whether a fully realized learning health care system can actually be implemented in an ethically acceptable way and will realize the benefits it's intended to realize." Menikoff noted that learning health care systems are not likely to eliminate ethical issues tied to research, including when informed consents are necessary. "Lines will have to be drawn and these difficult issues will not necessarily go away with a learning health care system," he said.
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Leiter noted that patients are increasingly sharing their health information themselves, and such patient engagement might substantially lower the inherent risk and potential for violation of patient expectations. She suggested less reliance on informed consent for uses of data in a learning health care system that would be considered "routine," and that we should instead pursue other models of patient engagement to enhance protections for research participants.
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She noted if a hospital doesn't need to get IRB review when deciding to switch brands of antibacterial soap, why should they need IRB review if they want to do a study comparing two brands of antibacterial soap, or two types of dispensers? Hospitals often arbitrarily adopt a new diagnostic assay as a routine procedure or change the duration of a routine procedure, such as dialysis, without any oversight, but when they wish to study the effectiveness of those measures, should their studies undergo IRB review?
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Such monitoring may or may not be needed for pragmatic trials, according to Ellenberg, but if it is done, the same principles and practices of data monitoring would be applicable to pragmatic trials. She speculated that "most pragmatic trials will require this monitoring because they are going to be addressing public health questions and will probably be fairly large." Because pragmatic trials are likely to be conducted on a more heterogeneous population than explanatory trials, researchers need to be more cautious about interpreting a "no difference" finding in their pragmatic comparative effectiveness studies.
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Several deficiencies in oversight of multisite studies were pointed out by speakers at the workshop. These deficiencies included clinical trial launch delays and inefficiencies due to multiple IRB reviews, conflicting IRB reviews and no standards for a high-quality IRB review, increased complexity and length of consent forms reviewed by multiple IRBs, and the impracticality of IRB reviews of clinical studies on rare diseases.
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Daugherty countered that studies indicate that IRB reviews are not the only reason for delays in study onset, nor are they necessarily the "rate-limiting step" for launching a clinical trial. Schilsky agreed, but stressed that IRB review can be a significant contributor to delays, which could be substantially reduced through greater use of central IRBs (CIRBs, see section on "Central IRBs")
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From a patient perspective, the variable quality and extent of local IRB reviews can be unethical, Collyar pointed out. Multiple IRB reviews typically make the consent form longer and more complex, Schilsky added, which might increase risk to patients.
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We need a regulatory framework that will encourage site acceptance of CIRB review as well as additional research on the appropriate metrics to define what a high-quality IRB review is." Parda agreed with many of the disadvantages of local IRB reviews cited by others at the workshop and added a few additional ones. He noted that local IRB reviewers tend to have limited reviewer expertise, and it can be a challenge to recruit and retain members and fund their work.
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The disadvantages he cited for CIRBs included the perception that their highest priority is activating the trial, rather than protecting research participants. There also are concerns that a CIRB cannot review protocols for local content, laws, and compliance as effectively as local IRBs, and that there might be increased potential for institutional liability through loss of control of the IRB review.
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With NCI's CIRBs, it is also no longer necessary to complete multiple IRB application and submission packets, and unlike local IRBs, the CIRB has some leverage to make a substantive change to the protocol, if necessary. But Parda added that there are still challenges involved in using NCI's CIRBs, including balancing local and central leadership and cultures.
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Duplicative IRB reviews are eliminated entirely once the reliance agreement is accepted. This system, which is flexible and scalable, promotes collaboration and reduces administrative burden and the costs for the IRBs and study teams, Bierer noted.
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Daugherty also pointed out that when CIRB reviews are done, local institutions will still need to support protocol and consent tracking, and monitoring of conflict of interest. With a CIRB review, the cost of local oversight will go down, but it isn't going to go down to zero, he said.
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He described an anecdotal experience in which he said the NCI CIRB spent less than 5 minutes discussing an annual review of two large Cooperative Group trials, encompassing more than 2,000 subjects, and thousands of adverse event and toxicity reports from dozens of local institutions. He noted that in the absence of local IRB review, there would be no other review of such ongoing research.
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Steven Piantadosi, Phase One Foundation chair and director, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, asked if a downside to using a CIRB would be that it would cause atrophy in the expertise and ability of local investigators in state-of-the-art research. Schilsky responded that institutions will still conduct scientific reviews of every clinical trial they offer, even if it undergoes CIRB review, so faculty members at those institutions will have the opportunity to serve on such review committees.
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"Physicians tell me they have little training in how to present consent forms to their patients," Albrecht said. Paasche-Orlow suggested doing a national survey of the training, supervision, and documentation approaches that are already being used in the consent process and using best practices, especially those rooted in the "teach-to-goal" approach to develop a model training program with teacher guides that can be applied across organizations (see Box 3)
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RESEARCH NEEDS Several speakers noted a lack of empirical evidence in a number of areas related to protections for research participants, including whether changes to the HIPAA Privacy Rule and guidances have improved patients' trust, what consent forms and processes are most effective, what the public thinks about sharing biospecimens and linked data, outcomes of returning individual genetic results to research participants, and the impact of CIRBs. Botkin noted that the informed consent process was not evidence based when it was first instilled within the regulations and it is still not evidence based as it is currently conducted.
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A regulatory structure that's based on legalistic fears of rare events may not benefit the mission to prevent and cure cancer and as we heard from our patient advocates, it will not help our patients." She added that a recurring theme throughout the workshop was to encourage a culture change of risk-based oversight that may need to consider innovative ways to approach informed consent. "We heard from our patients and advocates that they are concerned with what we don't do with the gifts and resources that they provide more so than information on other risks that we sometimes outline in multipage consents." She added that is not to say there are no risks in clinical research, but to recognize that the degree of those risks varies depending on what type of study is being done and in what type of context.
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2003. The effects of local review on informed consent documents from a multicenter clinical trials consortium.
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2001. Quality of informed consent in cancer clinical trials: A cross-sectional survey.
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2008. Nationwide privacy and security framework for electronic exchange of individually identifiable health information.
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