Editorial Views  |   December 2006
Do the Right Thing (or Do the Market Exclusivity Thing?)
Author Notes
  • “P Less Than” Company, San Francisco, California.
Article Information
Editorial Views / Pediatric Anesthesia
Editorial Views   |   December 2006
Do the Right Thing (or Do the Market Exclusivity Thing?)
Anesthesiology 12 2006, Vol.105, 1074-1075. doi:
Anesthesiology 12 2006, Vol.105, 1074-1075. doi:
(IF the title makes no sense, be patient.) In the current issue of Anesthesiology, Petroz et al.  1 describe the pharmacokinetics (and, to a limited extent, the pharmacodynamics) of dexmedetomidine in pediatric patients. When dexmedetomidine was approved by the US Food and Drug Administration (FDA) for use in adults in 1999, the package insert did not offer any guidance regarding its use in pediatric patients. In the ensuing years, little has been published about the use of dexmedetomidine in infants and children. I make no judgment as to whether the drug is useful in these patients; however, if a clinician believes that dexmedetomidine would benefit his or her patient, it is difficult to obtain either guidance on dosing or a perspective on the risk–benefit ratio in children.
During the 1990s, the FDA struggled with the infrequent submission of efficacy and safety data in pediatric patients. Although many drugs were used off-label (i.e.  , in the absence of language in the package insert describing use in a particular population) in children, dosing recommendations were often anecdotal, based on publications that may or may not have been peer reviewed. Despite journals’ interest in rigorous review of data submitted for publication, reviewers’ access to data (particularly that regarding safety events) is far more limited that the scrutiny the FDA applies in its reviews of clinical trials. Thus, it is not surprising that the FDA does not allow claims in package inserts based on nonaudited, published clinical reports. To improve package inserts for pediatric patients, the FDA created the “Pediatric Rule” in 1999; Congress passed the Best Pharmaceuticals for Children Act in 2002.1These initiatives informed the pharmaceutical industry that drugs that were likely to be used in pediatric patients required appropriate labeling, supported by clinical studies in the target population. As recently reviewed by Shultheis et al.  ,2 the FDA’s rules for pediatric labeling have undergone repeated challenges and revisions. However, currently, unless a drug has no potential benefit in children (e.g.  , a chemotherapeutic agent for prostate cancer), pharmaceutical companies are expected to perform studies in children, typically after approval for use in adults. In exchange for these efforts, the government offers an enormous carrot: 6 months of additional market exclusivity (i.e.  , thereby delaying generic competition). For drugs with annual sales of hundreds of millions of dollars, the additional period during which generic competitors can be excluded from the market represents a massive financial opportunity. In turn, many companies have performed pediatric studies to obtain this market exclusivity.
Why don’t pharmaceutical companies do studies in children early and often? My two-decade experience as an academic pediatric researcher (6 years ago, I changed careers; I now consult for pharmaceutical companies) may provide some insight. Conducting studies in pediatric patients is not easy. Obtaining consent from pediatric patients was challenging in my era; I suspect that it is markedly more difficult in the current environment: Petroz et al.  1 report that they were able to obtain consent from only 1 of every 20 families that they approached. Second, the environment for the conduct of clinical studies in anesthesia has become more problematic with each passing year. When I started doing clinical trials in 1981, delaying the start of surgery or end of anesthesia by several minutes or more to permit data collection for a clinical trial was accepted readily by my surgical colleagues; the nursing staff and hospital administration never paid any attention. In the current cost-containment environment, I doubt that investigators are allowed any delays in the surgical schedule. Third, investigational review boards at academic institutions (at least mine, the University of California, San Francisco) supported the conduct of clinical trials in neonates, infants, and children; in particular, we were not burdened by consent forms that were so onerous that family members would automatically refuse to participate. Today, as a consultant to industry, I see consent forms exceeding 20 pages and listing so many potential risks that one can readily imagine a reflex refusal from family members. Finally, many university-affiliated pediatric anesthesia departments focus heavily on clinical care (or basic research) rather than clinical research, affording pediatric investigators relatively little opportunity to develop research careers.
Other than the opportunity for market exclusivity (and “doing the right thing”), there may be little incentive for pharmaceutical companies to perform studies in children. First, for many drugs, sales in pediatric patients will be relatively small, a combination of the relatively small number of pediatric patients and the dose per utilization (as a function of size). Second, in many instances, investigators (typically in academic settings) obtain experience and then publish (or otherwise publicize) their results, providing the clinical community with guidance on dosing and adverse effects (although, as mentioned previously, without the scrutiny that would be applied by the FDA), and the drug is used extensively in children without appropriate labeling. A few examples are evident in the anesthesia community. In 1981, Organon asked me to determine the clinical pharmacology of vecuronium in infants and children. Our study included patients as young as 7 weeks of age,3 leading to the following text in the package insert: “See DOSAGE AND ADMINISTRATION: Use in Pediatrics subsection for recommendations for use in pediatric patients 7 weeks to 16 yr of age. The safety and effectiveness of vecuronium in pediatric patients less than 7 weeks of age have not been established.”2Although that package insert has not been revised to describe use of vecuronium in neonates, I suspect that clinicians were not deterred from its use in that population. Similarly, the fentanyl label reads “safety and efficacy of fentanyl citrate in pediatric patients under two years of age has not been established”3; despite this, fentanyl (and other members of the fentanyl family) are used widely in neonates and infants, guided by numerous publications in journals such as Anesthesiology.
Now back to the title of this editorial. I don’t know whether Abbott’s sponsorship of a study of dexmedetomidine in pediatric patients was “doing the right thing” or attempting to extend its market exclusivity (and hence it profits). Regardless, publication of the study should remind members of the clinical community of the need for high-quality pediatric research to ensure that infants and children can be treated safely and effectively with the full armamentarium of drugs available for adults.
“P Less Than” Company, San Francisco, California.
Petroz GC, Sikich N, James M, van Dyk H, Shafer SL, Schily M, Lerman J: A phase I, two-center study of the pharmacokinetics and pharmacodynamics of dexmedetomidine in children. Anesthesiology 2006;105:1098–110Petroz, GC Sikich, N James, M van Dyk, H Shafer, SL Schily, M Lerman, J
Shultheis L, Mathis LL, Roca RA, Simone AF, Hertz SH, Rappaport BA: Pediatric drug development in anesthesiology: An FDA perspective. Anesth Analg 2006; 103:49–51Shultheis, L Mathis, LL Roca, RA Simone, AF Hertz, SH Rappaport, BA
Fisher DM, Miller RD: Neuromuscular effects of vecuronium (ORG NC45) in infants and children during N2O, halothane anesthesia. Anesthesiology 1983; 58:519–23Fisher, DM Miller, RD