The FDA is aiming to clarify the ethical considerations in clinical trials with paediatric populations. With its recently announced draft guidance, the agency is setting boundaries for sponsors and institutional review boards (IRBs). However, the guidance’s vague language is repeating steps that the industry already takes.

Rather than presenting a regulatory change, the guidance’s intent is to offer support for interpreting and applying existing regulations using a contemporary ethical framework, with attention to the evolving complexity of clinical research, says Dr Naomi Laventhal, clinical associate professor at the department of paediatrics in University of Michigan.

However, a majority of the points made in the guidance are already used in clinical trial practice, says Dr Daniel Benjamin, professor of paediatrics at Duke Clinical Research Institute, adding that most of it was worked out 20 years ago.

Guidance for newcomers and the FDA itself

Questions have arisen about why the guidance was even drafted, if what it proposes is already used in practice. When asked what triggered the draft of the guidance, the FDA’s press officer directed Clinical Trials Arena to the announcement of the guidance and an FDA podcast, noting the parts discussing historical misrepresentation and the agency’s perspective on ethical considerations.

Benjamin says that the guidance will be useful both for pharmaceutical companies that do not have in-house paediatric experience and to train new professionals. “This guidance will help to minimize the repetitive conversation between experienced investigators and pharma companies, and will help shape less experienced investigators,” he notes.

The FDA might also be carving out the paediatric space in-house, says Dr Barry Mangum, senior vice president of paediatrics at Premier Research. Benjamin agrees and adds that while some FDA divisions have great expertise in the paediatrics, new employees or smaller divisions will need this extra guidance.

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More details are needed

The FDA did a “pretty good job of laying things out in terms of the big picture”, but when zoomed in, the draft guidance lacks clarity, Mangum says. For example, line 342 indicates that the collection of adult data prior to the paediatric trial “may not always be necessary” if nonclinical testing or modelling and simulations are used. Mangum explains that adult data is often necessary to understand the drug’s behaviour and create simulations. “Some of the language is vague in terms of putting some notices that we have to do these studies, but it doesn’t really give us guidance on everything,” he notes.

Benjamin says that he would have liked to see the guidance outlining adolescent children (ages 12–17 years) participation alongside adults, as they typically have a very close response. For example, line 104 of the guidance document states that if a product is being developed for adults and children, adult data from effectiveness studies should be extrapolated to children. Laventhal says this concept is not new, but rather received attention as Covid-19 vaccines were being developed for progressively younger age groups. However, extrapolation parameters do not fit for all age groups, Mangum notes.

The enrolment of children of various ages in parallel should also be considered, Benjamin says. Now, it is common to see a stepwise age progression, similar to what was seen in the Covid-19 vaccine trials and different age groups. However, the same approach should not be repeated, he adds. “In a life-threatening illness with a lifesaving product, you have a delay, and therefore deaths of children directly related to study design,” he explains.

As of today, the FDA has received one comment that should be reflected in the draft guidance. John Mullahy, PhD, a professor of health economics at University of Wisconsin-Madison, points out that in line 375, the guidance document indicates that “clinical investigations involving children should be designed to maximize the amount of information gained and minimize the number of subjects involved”. Mullahy notes that information maximisation and subject number minimisation are two exclusive goals. “There are fundamental trade-offs between them that should be appreciated, and in reality, must be addressed head on. I recommend that the draft guidance be revised to reflect this,” he writes.

Mangum explains that the guidance took a “middle of the road approach” to set boundaries for the benefit and safety of children. Laventhal pointed out that it was meant to guide within the existing regulatory framework. The draft guidance’s feedback inbox is open for 90 days after its launch last week.