The FDA has issued a new draft guidance regarding research in children.
An accompanying press release states that we must protect children inadequately studied drugs and devices. To do so, we need to study those innovations in the children for whom they will be used. In the past, the FDA says, children were excluded from studies out of the mistaken belief that the risks of research were greater than the risks of inadequately studied interventions. Instead, this FDA press release argues, “Children can be better protected by including them in clinical research.”
I applaud that stance. I’ve made similar arguments. I expected the FDA to acknowledge and address some of the unique challenges in developing and evaluating treatments for rare diseases. But the guidance itself doesn’t break new ground or address looming controversies. Instead, it summarizes currently existing guidelines. They distinguish between research that offers a prospect of direct benefit and research that offers no such prospect. When there is no prospect of direct benefit, risk must be minimal (or a minor increase over minimal.) When the child may benefit from being in the research, then the risks must be balanced by potential benefits. They summarize the guidelines for approving each type of research.
However, it is not always clear how to determine whether the research does or does not have the prospect of direct benefit. In some of history’s most controversial pediatric research protocols, this was precisely the issue. Krugman claimed that “the primary objective of (the Willowbrook hepatitis studies) was to protect the children.” Critics disagreed. The investigators in the SUPPORT study of oxygen saturation targets in premature babies saw themselves as primarily committed to the well-being of each child in the study. Critics disagreed.
These ethical conundrums will soon get much more complex. Drugs for rare conditions must be evaluated in very small populations of patients where traditional study designs are often infeasible. Companies want to manufacture and market these drugs. Doctors want to study them. Parents want such treatments and advocate for the approval of new drugs even when the evidence of benefit is minimal.
The current framework for oversight of research in children isn't designed for these challenges. It evolved over the last fifty years. It is based upon a fundamental (though not strictly dichotomous) distinction between research and clinical practice. Over the years, though, that distinction has become quite blurry. Most experimental treatments are studied because researchers think that they offer some prospect of benefit to children to whom they are offered. The problem is not in identifying benefit as a goal but in deciding whether the likelihood of benefit is sufficient to justify to largely unknown risks of clinical treatments.
Over those same fifty years, clinical practice has changed dramatically. The typical physician today is part of a healthcare team that includes many other responsible clinicians. Often, they a work for a corporation or health system that is subject to intense competitive pressure. Physicians and their employers pay exquisite attention to financial margins and performance metrics. Such systems increasingly emphasize the (research-like) use of data to measure quality, encourage efficiency, ensure safety, and guide a standardized approach to clinical care. Such systems also create conflicts of interest for doctors, whose loyalty to patients may be compromised by the need for efficiency and profit maximization.
The result of all these changes is that neither research nor clinical practice are what they were. Research is no longer uniquely risky. Unstudied innovation is riskier. Clinicians have new and often non-transparent conflicts of interest. In today’s complicated world of innovative health delivery systems and innovative biotechnology, data collection and analysis are essential to improve treatment of both current and future patients. Everybody is, in essence, a research participant. Both researchers and clinicians must balance their more obligations to patients with their other interests.
The FDA has been more innovative than this new draft guidance acknowledges. Throughout the COVID-19 pandemic, they have made use of Emergency Use Authorizations tied to demands for ongoing data collection. These partial approvals acknowledge the complexity of the current evidence-generating ecosystems and the fluidity of the borderline between innovation and clinical practice. These innovations suggest the way forward as we face the challenges and opportunities of medicine in the 21st century.
You can read and comment on the FDA draft guidance.