Informed Consent, Inclusion Prioritized in Revised Ethics for Human Trials

The World Medical Association (WMA) voted unanimously today to approve revised ethical principles for human participants in medical research.

Updates to the WMA “Declaration of Helsinki” (DoH) include:

• Respecting “individual autonomy” through “[f]ree and informed consent” that is given voluntarily by the person who will participate in the research
• Replacing the term “physicians” with “physicians and researchers” to incorporate the broader healthcare community
• Addressing structural inequities in medical research by “carefully consider[ing] how the benefits, risks, and burdens are distributed”
• Weighing the harms and benefits of research inclusion and exclusion criteria to avoid perpetuating or worsening disparities in already vulnerable populations
• Seeking informed consent from the legally authorized representative for participants who are “incapable of giving free and informed consent”

The DoH was simultaneously released in JAMA. In an accompanying editor’s note, Jack S. Resneck Jr., MD, chair of the WMA work group, explained that the WMA was created “in the wake of historical abuses and violence committed under the guise of scientific research,” and that the DoH “was the first set of international ethical principles guiding medical research involving human participants.” The declaration was adopted in 1964 and is revised roughly every decade. The declaration was last amended in 2013.

In an interview with MedPage Today, Resneck, who is at the University of San Francisco School of Medicine, highlighted other updates in the guidance. For instance, the term “subjects” has been replaced with “participants” to reflects that people who take part in trials are “partners and co-creators in research,” he said. The updated DoH document also has a more pronounced focus on “meaningful engagement” with participants that addresses research in the context of structural inequities, Resneck stated.

While encouraging community engagement is not a “brand new” concept in research, “it wasn’t fully reflected and installed as a core ethical principle in this document,” previously, he said. “That’s a big change.”

Resneck also emphasized that the updated DoH focuses on “responsible inclusion.” In the past, vulnerable communities may have been excluded from research by default, he explained. “That’s very understandable…because we have seen vulnerable groups harmed in the past when ethical rules were not followed.”

But that approach has “actually exacerbated disparities, and we end up in a world where we have way less information, for example, on how treatments work in women and children, and historically marginalized groups and that is not helpful,” he said.

“If you’re going to advance public health, we need human participants to participate in clinical trials and other medical research … but we also have to do it in a way that fully respects the dignity and the rights of all of those individual participants,” Resneck said. The goal with “responsible inclusion” is to include vulnerable groups and incorporate special protections and supports for them, he stated.

Of course, the DoH was informed by the COVID-19 pandemic. One stakeholder session in Tokyo looked solely at research in the context of a public health emergency. As a result, the DoH now includes “brand new language” to reflect that every one of its principles still holds during a public health emergency, Resneck said.

“There can be innovation…in how research is conducted during a public health emergency, that can allow things to go faster … [and] to get things out more quickly through publication and peer review… than we’re used to,” he said. However, Resneck also emphasized that “there are no shortcuts to protecting individual research participants…that’s so critical to maintaining the public’s trust in the medical community and the medical research enterprise.”

Other aspects of the declaration that Resneck noted are:

• “Free and informed consent:” Participants may opt to participate in studies with low personal benefit but greater societal benefit, such as vaccine studies or phase I trials. “It’s really important to the declaration to articulate this importance of protection of individual participants as a paramount feature and a paramount principle,” he said. “This document…lays out those high level principles.”
• Unproven therapies: The previous DoH described the off-label use of medications when no other treatment is available, but Resneck said that was misinterpreted by some researchers to defend the use of drugs even when it was “pretty clear that they didn’t work.” The updated version clarifies that “nobody should should abuse that option in order to try to get around the protections of the declaration.” Patients who are getting unproved therapies still need to be informed of the risks and benefits, he said, and the “use of that drug in that patient should be studied so that others can benefit from the knowledge.”
• Personal data storage: “The workgroup recognized a lack of adequate reference to consent requirements and participant protections for the growing use and associated risks of personal data stored after trials, especially given the emergence of augmented intelligence, machine learning, genetic data collection, capacity to reidentify deidentified data, and commercial and political data misuse,” he wrote in the editorial comment. Language in the amended DoH calls for “free and informed consent for the collection, processing, storage, and foreseeable secondary use of biological materials and data and for ethics committee approval and monitoring of such databases,” Resneck wrote.
• Independent ethics committees: The DoH calls for adequate resources, training, and education for these committees. It also recommends having at least one public member to “capture that input from outside the research enterprise,” Resneck said.

Asked if the DoH update had gotten any pushback, Resneck noted that “stresses and tensions” are inherent to bioethics. But the 30-month process to review and revise the DoH involved multiple stakeholder sessions around the world, along with two extensive public comment periods. The 2024 DoH has received “overwhelming support,” indicating that the changes will make it “relevant for the next decade ahead,” he said.

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