A balancing act: Innovating IRBs for the future of pediatric oncology research

The race to evaluate investigational cancer therapies requires an urgent need to enroll as many participants as possible, yet sponsors and their institutional review board (IRB) partners a unique balance when protecting children in pediatric oncology clinical trials.

Since Dr. Sidney Farber launched his battle against childhood leukemia in the late 1940s, the battle against pediatric cancer has continued charging forward. Over the last eight decades the FDA has approved more than 50 drugs, with over 70 indications, to treat cancer in children. More than half of these drugs have been approved in just the last decade, in large part due to the passage of two critical pieces of legislation: the Pediatric Research Equity Act and the Research to Accelerate Cures and Equity (RACE) for Children Act, which mandate that newly developed oncology drugs be tested in children.

While this recent acceleration in the fight against pediatric cancer is encouraging, challenges persist with enrolling children in clinical trials, threatening to quell this progress. Pharmaceutical companies and trial sponsors racing to evaluate investigational cancer therapies have an urgent need to enroll as many participants as possible into their studies. Yet, at the same time, sponsors and their institutional review board (IRB) partners face their own unique challenges in balancing the critical need to enroll participants in studies and advance pediatric research with the responsibility to ensure that these studies protect the children who participate in them.

Striking this delicate and often difficult balance requires an exceptional level of care and attention to detail. The regulations governing pediatric research (i.e., Subpart D of the “Common Rule” and FDA regulations) require pediatric research to fit into one of four buckets to be approvable by IRBs but discerning this can be difficult. It involves the ability to make nuanced judgments about both risk-level and benefit. The line between adequately protecting children, on the one hand, and over-protecting them, on the other, is not always clear. In addition, there is vagueness over what is required to adequately inform children about research and secure their voluntary assent. To continue to push ahead in this relentless battle against pediatric cancer, the industry must innovate and evolve how it thinks about these issues and manages the process.

“Most trials have significant risks, so we need to look very carefully at the inclusion and exclusion criteria and ensure that we exclude patients that might not tolerate the new drug while also making the trial general enough for as many participants as possible,” said Laura Campbell, a former pediatric oncologist who now participates in an independent IRB. “To be sure, it’s a difficult balance.”

That challenge begins with the informed consent process, an already complicated procedure that is made even more difficult by the complexities inherent in most pediatric oncology trials. The informed consent process remains one of the biggest issues with clinical trials and by far the most common issue raised by U.S. Food and Drug Administration (FDA) inspectors in an analysis published in the Journal of Pharmacy & Pharmacognosy Research. At least 14% of the inspection and non-compliance documents cited in that study relate to a “failure to obtain proper informed consent from study participants.”

“Trial participants and their guardians need a complete and thorough understanding of the trial, including its risks and benefits, to make a truly informed decision,” Campbell said.

But beyond receiving consent from an adult guardian, there is also the need for ‘assent’ from the pediatric patient. A trial protocol must be designed in such a way to recognize children’s autonomy and the requirement for assent is a crucial part of this, giving child participants the opportunity to understand the study and what will be required of them and voice any concerns.

Children and teens may decline participation for reasons that are not top of mind for adults – such as a protocol that might require them to have blood draws, an intravenous port, or even to lose their hair – making it even more crucial for trial investigators to carefully and thoroughly explain the potential benefits and risks in a manner that makes sense to them.

Moreover, the minimum age for a child’s assent, and the way in which that assent is obtained, is not specifically addressed by the federal regulations governing research in the U.S. (Common Rule (CR)) opening the door for ambiguity and variability between IRBs and institutions about how to operationalize the assent process. The way individual investigators approach assent conversations with children might vary dramatically. This, in turn, increases the risk of influencing the child one way or another. While some influence is unavoidable and benign, investigators must be sensitive to the impact that their word choices can have on a child and strive to be as unbiased and impartial as possible. Yet even decisions that are not directly tied to the assent conversation, such as process and personnel decisions, may unintentionally encourage or discourage a potential trial participant.

It is critical that IRBs do their best to ensure that the conditions for undue influence are minimized during the consenting process. They can do this by careful review of the consent form to ensure that the possible benefits are described realistically and not embellished or over-promised. Further, IRBs can actively remind researchers of the importance of avoiding undue forms of influence with vulnerable populations, including children, by seeking attestations to this effect as part of the IRB study submission process. While the IRB’s role is important, ultimately, researchers bear responsibility for ensuring that they avoid undue influence in their actual interactions with child patients.

Even prior to assent, IRBs must be confident that the study does not present unacceptable risk for children, and that offering them a choice to participate is reasonable. Additionally, IRBs must be certain that investigators understand what information is essential to convey to the child and what is not. However, this depends on the study and is often subjective, as IRBs and investigators can differ between and among themselves over what should be considered important. This introduces variability into what should ideally be a highly controlled process.

To be sure, it’s a difficult tightrope to walk, but there are some steps to take now to begin improving the process:

1. Present key information to participants more clearly.

Consent forms for pediatric oncology studies can stretch on for page after mind-numbing page, making it difficult for even the most informed trial participants and their guardians to understand what the true risks for a study are.

“The best consent forms include a one-page summary and an appendix,” Campbell explained. “The risks of the investigational product should ideally be emphasized and placed in the foreground, with the risks of any FDA-approved or standard-of-care therapies reserved for disclosure later or in an appendix.”

This approach helps to provide a clear picture of the risk involved without drowning potential participants in information, which ultimately helps everyone involved. It is supported, too, by the recent revisions to the Common Rule, which require consent forms to begin with a brief “Key Information” (KI) section that distills important details and helps individuals think through reasons for and against participating. As the FDA moves toward harmonizing, soon such sections may be required on consent forms for all regulated research in the United States.

Even so, KI sections need improvements, including:

• Distill language to be shorter and more concise
• Simplify, writing at age-appropriate reading levels
• Increase readability by following good literacy principles (i.e., proper spacing, font, graphics, etc.)
• Improve relevance and usefulness – for instance, provide participants with participation risks, possible alternative treatments available to them outside of the study, time commitments and cost, up front, so they can make a more informed choice.

It is also important to note that this is relevant for both assent forms given to children and informed consent forms given to guardians – both need to do a better job distilling and presenting useful information up front.

2. Streamline the IRB review process.

The IRB review process has traditionally been long and arduous to complete, often taking weeks. This outdated paradigm has become untenable and must change to more effectively enroll participants and move studies forward faster. Much in the same way that we need to improve the consent and assent processes, we also must make the IRB process nimbler and more efficient without sacrificing thoroughness and quality. There are some important challenges, here, though.

Regulations governing pediatric research are complicated and it is not obvious how to interpret them. They only permit studies to be approved by IRBs when they fit into one of three categories: they must either be (1) minimal risk, (2) hold a prospect of direct benefit and be such that those benefits balance the risks, or (3) for studies that are greater than minimal risk and do not hold benefit for the child (i.e., that do not fit into first two buckets), they must pose “no more than a minor increase over minimal risk” and stand to produce important generalizable knowledge.

There is a lot of ambiguity, debate, and variance over how to interpret these categories. For instance, how is ‘minimal’ risk defined? At what point does a trial become more than minimal risk? And, what exactly should be considered as providing a ‘direct benefit’ to child participants? Does providing additional standard care count, or should we just consider possible benefit from an investigational therapy? What about payment or incentives? And what on earth does “no more than a minor increase over minimal risk” mean or look like?

If IRBs want to navigate these waters and make sound and efficient regulatory decisions that both permit important research to proceed while respecting regulations and ethical norms, they need a principled approach and training on how to understand these concepts. IRBs need to carefully think through the best interpretations of the regulations and ensure they are applied consistently. Regulators should help, too. Currently, the FDA has a draft pediatric guidance, but IRBs need more assistance from regulators on how to understand and interpret the pediatric regulations.

3. Ensure the right team is in place and embrace researchers as collaborators.

For IRBs to successfully carry out their mandate to protect pediatric participants – and to do so as efficiently as possible – they must be comprised of a diverse range of experts. Medical doctors and scientists who understand the clinical risks, of course are critical, but also non-scientists, such as members of the community (teachers, pastors, etc.), ethicists, and technology experts, all have important roles to play in assessing risk for children of different ages.

“A board of various experts can make sure that the right HIPPA language is included in an informed consent, for example, or that certain site-specific requirements are met,” Campbell said. “Also, IRBs with widespread and diverse resources ensure that staff carefully review forms with a fine-tooth comb and from different points of view before it gets to the reviewer.”

This is where independent IRBs can be particularly useful, by having the familiarity and knowledge that develops over repeated experiences reviewing research protocols and the personnel depth to secure adequate expertise across therapeutic areas. Specifically in pediatric oncology trials, independent IRBs can ensure that seasoned practitioners with firsthand experience caring for their young patients – i.e., pediatric oncologists, clinical and research nurses, and other support staff such as counselors and chaplains – review the study and are present at the meeting. The presence of these individuals is essential to ensuring that the IRB has the scientific, medical, and psycho-social context needed to provide quality ethical review of specific studies.

While the IRB reviews documents (protocols and consent forms) and ensures that they conform to ethical norms, this is where their job typically ends. The IRB is typically not on the ground as the research unfolds, making sure that the protocol is followed, the study team is discussing the consent/assent document and answering questions properly, or that ethical norms are followed. This is where the site investigator plays a significant role. No matter how good the IRB review is, the rights and interests of children participants will not be honored unless the investigator is committed to doing so.

Unfortunately, IRBs and research teams have been seen as antagonists. Research teams traditionally see IRBs as a potentially negative force to be guarded against rather than as partners. But when it comes to children in cancer trials – arguably the most sensitive and delicate research situations – IRBs need to recognize their role as collaborators to ensure children are treated well by diligently educating investigators and study teams about the nuts and bolts of research ethics and oversight. IRBs and investigators must approach these trials, especially, as one, collaborative team and have the best interest of pediatric participants at heart.

Ensuring ethical and efficient pathways in pediatric oncology trials

Navigating the complexities of pediatric oncology trials demands both the ability to accelerate innovative medical advancements while also safeguarding young participants. It’s no easy task. But by creating more clarity in consent processes, streamlining IRB reviews, and assembling multidisciplinary teams, we can begin to make important strides forward in our ability to overcome this unique challenge and adapt to the evolving landscape of pediatric cancer research.

Ultimately, by embracing both collaboration and innovation – two critical components that helped to spark Dr. Farber’s own efforts against pediatric cancer decades ago – we can continue to refine our pursuit of these groundbreaking treatments that will benefit countless children now and for years to come.

Luke Gelinas, PhD, is Senior Chair Director at Advarra.

Lead photo, DEPOSITPHOTOS@ ivelin