William R. Sexson M.D.,and Deborah Cruze J.D., M.A.

Historically, pharmaceutical manufacturers have chosen not to test most drugs on children or adolescents. Children make up a relatively small section of the market, raise safety concerns as vulnerable subjects, and provide little financial incentive to drug companies to develop drugs for them. Prior to 2003, Food and Drug Administration (FDA) requirements allowed drugs to be approved solely for adults. This caused a number of problems for physicians who treat children and adolescents. Seventy-five to 80 percent of drugs approved prior to 2003 have not been specifically tested nor approved for pediatric use. Despite this, physicians are frequently in a situation where the most appropriate therapy would be a medication which can only be prescribed “off-label.”

Off-label prescribing is the practice of prescribing a drug either for a purpose different from indications for which the drug was FDA approved or for a different patient population than that approved by the FDA. This off-label use is extremely common in pediatric patients and frequently an essential part of the medical armamentarium in treating pediatric diseases. Although allowed by FDA law and regulations, off-label use raises many of the ethical questions frequently associated with experimentation in children. That is, there may not be the usual safeguards designed to protect human subjects. Specifically, there is little information as to the material risks and benefits of the medication; there is no assurance of informed parental decision-making; and alternative therapies may not be discussed.

Both therapeutic and ethical tension exists when the infant or child has a disease process which needs treatment, and when the only (or at least apparently the best) treatment available is a medication which has not been approved for use in children of that age. The lack of information gives rise to those classic questions that are at the root of most clinical ethical issues: What is the “best” (most beneficent) course of action? Will we be able to balance the benefit and risks of treatment (or lack of treatment) such that we avoid harm (nonmaleficence)? How do we fulfill our fiduciary responsibility in assuring that the patient and the family are properly informed about the disease process, the goals of care and the burdens and benefits of treatment or lack of treatment? How do we assure that the patient and family arrive at their own decision about their care (autonomy)?

Many ethicists feel that prescribing off-label is a form of experimentation. Although it might be inferred that an off-label drug can be used in the same dosage range with similar efficacy as well as similar adverse effects, this inference is relatively empiric and not strictly consistent with “evidence-based” practice. Therefore, the off-label use of a medication becomes a form of individualized trial. Research on human subjects is governed by the National Institutes of Health-sponsored “Belmont Report.” In this report, federal agencies were directed to consider four basic issues: 1) the boundaries between biomedical and behavioral research and routine medical practice; 2) the role of risk-benefit assessment in research involving human subjects; 3) developing human subject selection guidelines; and 4) the nature and definition of informed consent in various research settings.

The best research studies are obviously done prospectively, are randomized and are blinded such that there is little chance of specious results based on preconceived notions. Similarly, obtaining the informed consent of the parent and the assent of the child, (for children ages seven or above) is an important ethical requirement of human research. Information regarding the risks and potential benefits of the drug must JANUARY/FEBRUARY 2006 35 be provided to the parents and child. The research is subject to approval and review by the Institutional Review Board (IRB) which also generally provides on-going oversight of the research study. This research methodology and these safeguards may not be present when drugs are prescribed off-label.

Other potential concerns with off-label prescribing arise when one considers the practitioner’s source of much of their drug information. Specifically, many physicians get their drug information either from pharmaceutical company representatives or from drug seminars where the presenter is a physician paid for by the drug firm. In either of these situations, the presenter has a significant conflict of interest such that the information provided may be biased toward the use of the company’s drug. A further concern is that some insurers may avoid payment by denying reimbursement to the family for drugs that are prescribed “off-label.”

When using off-label medications, some practical ethical guidelines should include the following:

1. The physician should stay up to date with current medication information and current professional literature. Do not rely on pharmaceutical industry representatives as your sole source of medication related information. Periodically read the PDR or the drug information brochure contained in the medication packaging.

2. Inform the parents and the child (if of an appropriate age) about the disease process and decide on the goals of care.

3. Once the goals of care have been established, then discuss the options for treatment (or lack of treatment) and the benefits and risks of each. This discussion should include a discussion of the information, or lack of information, regarding the risks and benefits of off-label drugs.

4. Allow some time for the family and patient to discuss all of the above with some privacy, and allow them to arrive at a goal-based decision about the treatment plan.

5. Document your discussion in the patient’s chart.

A national effort to require pediatric studies for off-label drugs has been supported by the American Academy of Child and Adolescent Psychiatry, the American Academy of Pediatrics and the FDA. Congress passed the Food and Drug Administration Modernization Act (FDMA) in 1997. Re-authorized in 2002, the Act provides a financial incentive for companies to conduct studies with pediatric patients by extending the market exclusivity (patent) of the drug for six additional months. On December 3, 2003, the Pediatric Research Equity Act (PREA) was enacted. This Act requires that all applications for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration contain a pediatric assessment unless a waiver has been obtained. It also authorizes the FDA to require pediatric studies under certain circumstances. These efforts should lead to more knowledgeable prescribing of medication in children.


Dr. Sexson is a neonatologist and Associate Dean for Clinical Affairs at Emory University in Atlanta, GA. He is on the Board of the Emory Center for Ethics, and has published and lectured widely in the area of healthcare ethics.

Ms. Cruze is the Clinical Ethicist at Grady Health System in Atlanta, GA. Prior to this appointment, she served as an Ethics Fellow at the University of Texas, MD Anderson Cancer Center, in Houston, TX. She received her Master of Arts degree in Bioethics from Midwestern University after serving eight years as a City Judge for the City Court of Glendale, AZ. She has also served as an adjunct faculty member of various colleges and universities for the past 20 years.