By: Robert “Skip” Nelson, M.D., Ph.D.
Parents and guardians of seriously ill children often face difficult decisions about their child’s medical care. As a physician practicing for about 20 years in a pediatric intensive care unit, I knew that many of the interventions I used, while potentially life-saving, had no guarantee of success and carried a risk of significant harm or even death.
When faced with a life-threatening disease for which there are few good options, parents sometimes want to try a promising drug that is still under development. I have lived through this situation with parents many times, both in the intensive care unit and as a medical ethicist. Some parents see the drug as a lifeline where none had existed before. It is a natural instinct for parents to want to leave no stone unturned.
Many of the drugs that we use in children have not been approved by FDA for that use, and may not have been studied at all in children. They are available on the market because they have been studied and approved for use in adults, but not necessarily for the same disease for which they might be used in children. There are data available in adults describing the risks, benefits and side effects of drugs already in the marketplace. This information may reassure us a bit about the potential effects of a drug in children. But when that same drug is studied in children, we often discover that we should have been using a different dose, that the drug does not work, or that children may experience a concerning side effect.
The lack of information about the likely effects of a drug in children is more of a problem when the drug hasn’t yet been approved for any use. Most drugs in the early phases of drug development fail, either because they are ineffective in humans, or because of unacceptable side effects. So while it may be tempting to want to try any experimental drug in children with a life-threatening disease, we must be cautious.
Recently, my colleague Richard Pazdur shared his insight into the FDA “expanded access” regulations that allow patients with serious and life-threatening diseases or conditions access to investigational drugs outside of clinical trials. There are two important values at stake when considering expanded access in children. We want to do everything we can to restore a child to health, but we also want to protect that child, and other current and future children from ineffective, and potentially dangerous, interventions.
Physicians can apply for expanded access use for a patient by submitting certain medical information about the patient and important scientific and clinical information about the drug and its intended use to FDA. FDA then reviews this information and determines whether certain important criteria are met. These safeguards are in place to avoid exposing patients to unnecessary risks. Even if FDA determines that an expanded access request may go forward, the company manufacturing the drug has to be willing to supply it.
In implementing its expanded access regulations, FDA tries to strike a balance between two social goods: treating an individual child and demonstrating that a medical product is safe and effective. Children with a serious or immediately life-threatening disease for which there is no comparable or satisfactory alternative therapy are able to have access to investigational agents outside of a clinical trial. However, there must be some evidence that the potential benefit to the child justifies the risks of the treatment and that those risks are not unreasonable in the context of the disease to be treated. Providing the investigational drug must not interfere with the ability to initiate, conduct or complete a clinical trial of that drug that could be used to support its marketing approval for the disease. Otherwise, we would never collect the essential data needed to establish that the drug is truly safe and effective for that use, or whether one child’s seemingly miraculous response was the result of the drug or of something else.
FDA strongly supports the inclusion of children in FDA-regulated clinical trials, provided the trials are conducted in an ethical and scientifically sound manner. For the past 15 years, FDA has been actively involved in initiatives aimed at improving medical product research in children (including under the legislative mandates provided by the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act). Children must be protected from exploitation and exposure to unnecessary risks related to their inclusion in clinical research, and from the unwarranted use of investigational drugs outside of a clinical trial.
I am often asked about FDA’s role in protecting children who are receiving experimental treatments and who are participating in clinical trials. FDA’s regulations provide for specific additional protections to help ensure that children who participate in research are involved in ways that protect the children’s rights, safety, and welfare. Protections include, for example, review of research by an Institutional Review Board (IRB) supplemented by pediatric expertise as appropriate. The risks posed by research interventions must be low if the interventions are done for the sake of knowledge rather than for the child’s medical benefit. For higher risk interventions, the intervention must offer the child a sufficient prospect of direct medical benefit to justify the potential risks. Investigators must also obtain permission from the child’s parent(s) or guardian(s), and in most clinical trials must obtain each child’s assent when the child is developmentally capable of providing it.
My heart goes out to those parents of children with a life-threatening disease for whom there are no satisfactory treatments. My personal belief is that responsible clinicians and investigators caring for critically ill children, parents, and FDA can work together to find the right path forward for our present and future children.
Robert “Skip” Nelson, M.D., Ph.D., is Senior Pediatric Ethicist in FDA’s Office of Pediatric Therapeutics