Essentials document defines protocol ethics
Ethics Essentials gives researchers a reference
Developing a sound, ethical protocol is the top goal for any researcher or IRB. But the basic ethical elements and the considerations behind an investigator's choices may not always be clear, often resulting in back-and-forth discussions between investigators and IRBs reviewing the protocol. A group from Harvard University collaborated with other research stakeholders to develop an ethics reference tool for investigators.
The Multi-Regional Clinical Trials Center (MRCT) at Harvard University in Cambridge, MA, was formed to improve multi-regional trials, particularly in the developing world. The center seeks to improve transparency, establish best practices, develop standards, and improve the safety and efficacy of trials.
In planning meetings to develop initiatives for improving clinical trial standards in developing countries, MRCT's work group found that ethical elements are not always plainly expressed within a protocol design.
"One of the things that became clear is that there is very rarely an ethics section in a protocol that explains to IRBs, investigators, study staff and prospective participants how the protocol drafters address ethical questions, why they think their choices are the most appropriate, and how they arrived at their conclusions," says Barbara Bierer, faculty co-director and co-chair, MRCT Executive Committee, senior vice president of research, Brigham & Women's Hospital, and professor of medicine, Harvard Medical School. "Those considerations are embedded in the trial design, but rarely explicit."
Ethics Essentials tool kit
MRCT created the Ethics Essential Elements document as a reference for researchers to build a clear ethical framework and to further explain the rationale behind the study design. The tool, released in November 2013, was designed to help clinical researchers consider the ethical points of the protocol design and explain those elements to IRBs and other investigators.
"We thought if we made [ethics issues] explicit so that investigators understand the complex questions and considerations, they can address how they answered those questions and explain the ethics in the context of the protocol. It gives the ethics committee the opportunity to think through these same issues and analysis to agree, disagree, or look for further information," Bierer says. "At a minimum, such an approach will increase transparency and decrease the back-and-forth that so often occurs between ethics committees and the protocol drafters." It may also improve the efficiency and quality of IRB review, as ethical considerations are already developed and put in writing prior to submission, she says.
The document recommends that each protocol have a dedicated ethics section to address or cross-reference the essential elements. The tool names 11 elements of ethics, including the following:
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addressing relevant question;
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choice of control and standard of care;
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choice of study design;
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choice of subject population;
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community engagement;
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informed consent;
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potential benefits and harms;
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return of results and management of incidental findings;
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post-trial access;
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payment for participation;
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study-related injury.
Ethics Essentials includes two parts: the Ethics Tool Kit and the Ethics Essential Elements and Point to Consider Reference Document. The Ethics Tool Kit includes an introduction to the element, questions to consider and a space in which to write answers, examples of each element, and definitions of terms. The PDF document also contains hyperlinks in the table of contents and throughout each section for easier navigation. For example, Essential Element 1 defines a "relevant question" and explains the elements of a question. The Points to Consider sections asks: "Why is the development of this therapy needed? What is the unmet need? Explain the justification for this particular study." Hyperlinks within the section lead to examples of responses to the Points to Consider questions. The format, layout and logic, and interface of the document was enabled by a collaboration with Public Responsibility in Research and Medicine (PRIM&R).
The Points to Consider Reference Document gives additional resources and references. It gives examples of real-world situations for each essential elements, and links to past studies and guidances.
Defining the essentials
During the development phase of the tool, MRCT convened a multi-stakeholder group including IRB members, bioethicists, investigators, lawyers, regulatory agencies, investigators, protocol drafters and others involved in research to meet periodically and present ideas on the project. The group spent more than a year in meetings and teleconferences to define what it means to be an essential ethics element, and what should be included in the tool kit. "It took over a year to put these documents together in terms of having an approach, drafting the questions and considerations behind them, explaining what the issues were and developing the tools that we present," Bierer says.
"Everyone gave their ideas of what would be important enough to include," adds Jacquelyn Murphy, MPH, project manager/program administrator, MRCT. "They looked at what protocol documents included, what isn't touched on too much in the documents, and what they found to be glaringly absent. So there was a lot of thought when considering what elements we should include in the document."
While the ethics guidelines are written generally for any protocol, MRCT encourages their use in clinical research in developing countries. For example, the Community Engagement element defines key terms and points to consider for collaborating and engaging with host communities and minimizing exploitation. It explains the different ways in which the term "community" may be defined, and gives examples of who could be considered a community leader (e.g. elected mayor, tribal council). The Points to Consider section gives spaces for researchers to describe plans for consulting community leaders, developing informed consent that the community can understand, and plans for data access and dissemination of results to the population.
Although the Ethics Essential Elements was released only recently, Bierer and Murphy say there has been positive feedback. MRCT conducted a survey of small and academic research institutions to gauge the early interest in the Ethics Essential Elements. "A number have said they used our Ethics Essentials to modify their own checklists," Murphy says. "Even if they're not using the tool as presented, they said it helped their processes." The group plans to gather more data on the tool's usage and tweak the tool as needed. "We do want to improve this over time and make it more user-friendly," she says.
The center is also considering follow-up projects based on the tool kit, including projects centered on IRBs. "One of the things we're considering as a follow-up project is an ethical checklist for the IRB," Bierer says. "We have written a toolkit for the people who design the protocol and trial; we should also have a comparable framework for IRB analysis specifically for IRBs that have not developed their own tools."
