Clinical Trials of Drugs Used Off-Label in Neonates: Ethical Issues and Alternative Study Designs

Abstract

The use of drugs for indications unapproved by the Food and Drug Administration (FDA), often called “off-label use,” is widespread in children, including neonates. The widespread off-label use of drugs in neonates presents ethical and safety challenges. Since the passage of the Best Pharmaceuticals for Children Act (BPCA) in 2002, both the FDA and National Institutes of Health (NIH) have taken initiatives to facilitate and encourage research to achieve the necessary labeling for drugs routinely used in infants and children. Federal regulations provide broad rules and guidance for the protection of human subjects in research. However, there are ethical issues that a physician may face when designing clinical trials of drugs in neonates that are routinely used off-label and widely believed to be beneficial. We attempt to describe these ethical challenges and provide recommendations, including alternative study designs, to resolve them in an ethical framework that takes into account the Belmont Report, the statement of the World Medical Association (WMA), and federal regulations.

Keywords:

• active control
• alternative study designs
• clinical trials
• ethics
• neonatal emergency research
• neonates
• placebo
• off-label
• unlicensed

Acknowledgment

The work was done (SBA) as part of the clinical investigational training requirement for a Masters in Clinical Research Program and was supported by NIH K-23 DC 006229-02. Also, the article was supported in part by a grant from: Fogarty International Center/NIH 1R25TW007090-01 (AES), and by the University of Rochester Clinical and Translational Sciences Institute (CTSI) 1 UL1 RR024160-01 from the National Center for Research Resources, a component of NIH (MPM).

Notes

Food and Drug Administration (FDA) Modernization Act of 1997. (1998). FDA internet index of pediatric issues: FDAMA, 1998 final rule, label changes, exclusivity.

United States. Congress. Senate. Committee on Health Education Labor and Pensions. (2001). Best Pharmaceuticals for Children Act : report (to accompany S. 838). [Washington, D.C., U.S. G.P.O.