Anne Zajicek

Core outcome domains and measures for pediatric acute and chronic/recurrent pain clinical trials: PedIMMPACT recommendations

UNLABELLED Under the auspices of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), 26 professionals from academia, governmental agencies, and the pharmaceutical industry participated in a 2-stage Delphi poll and a consensus meeting that identified core outcome domains and measures that should be considered in clinical trials of treatments for acute and chronic pain in children and adolescents. Consensus was refined by consultation with the international pediatric pain community through announcement of our recommendations on the Pediatric Pain List and inviting and incorporating comments from external sources. There was consensus that investigators conducting pediatric acute pain clinical trials should consider assessing outcomes in pain intensity; global judgment of satisfaction with treatment; symptoms and adverse events; physical recovery; emotional response; and economic factors. There was also agreement that investigators conducting pediatric clinical trials in chronic and recurrent pain should consider assessing outcomes in pain intensity; physical functioning; emotional functioning; role functioning; symptoms and adverse events; global judgment of satisfaction with treatment; sleep; and economic factors. Specific measures or measurement strategies were recommended for different age groups for each domain. PERSPECTIVE Based on systematic review and consensus of experts, core domains and measures for clinical trials to treat pain in children and adolescents were defined. This will assist in comparison and pooling of data and promote evidence-based treatment, encourage complete reporting of outcomes, simplify the review of proposals and manuscripts, and facilitate clinicians making informed decisions regarding treatment.

Pharmacokinetics of oseltamivir among pregnant and nonpregnant women

We sought to delineate the pharmacokinetics (PK) of oseltamivir and its active metabolite oseltamivir carboxylate during pregnancy. Physiologic changes of pregnancy, including increased renal filtration and secretion, may increase the clearance of oseltamivir carboxylate. Sixteen pregnant women taking oseltamivir for prophylaxis or treatment of suspected/proven influenza infection were enrolled. Twenty-three nonpregnant reproductive-age females served as the control group. The primary PK endpoint was area under the plasma concentration time curve for oseltamivir carboxylate. Pregnancy did not alter the PK parameters of the parent compound, oseltamivir. However, for oseltamivir carboxylate the area under the plasma concentration time curve was significantly lower (P = .007) and the apparent clearance significantly higher (P = .006) in pregnant women compared with nonpregnant women. Pregnancy produces lower systemic levels of oseltamivir carboxylate. Increasing the dose and/or dosing frequency of oseltamivir during pregnancy may be necessary to achieve comparable exposure in pregnant and nonpregnant women.

Gaps in knowledge in treating pregnant women

Because studies are often undertaken without knowledge of the pharmacokinetics of a drug, efficacy is difficult to assess in pregnant women. To address this lack, basic and clinical research within the National Institute of Child Health and Human Development is focusing on expanding knowledge of pharmacology during pregnancy. Although medication use, including prescription, over-the-counter, and herbal products, is common during pregnancy, physicians may not be aware of the nonprescription products their patients are taking or the interactions these products may have with prescribed medications. A number of studies have found sex differences in oxidative metabolism and transport, as well as pharmacologic and toxicologic differences in hepatic metabolism, that are ultimately reflected in pharmacokinetics. Sex differences exist in distribution volumes, transport proteins, and drug clearance. Beyond these sex differences, pregnancy itself affects the absorption, distribution, metabolism, and elimination of a drug. Women experience more adverse drug reactions (ADRs) than do men, and these reactions tend to be more severe. QT prolongation (torsades de pointes) and hepatic toxicity are two of the most severe ADRs, frequently causing withdrawal of a drug from the market. Women may also metabolize drugs more quickly than do men, and drugs metabolized by cytochrome P3A4 are cleared more rapidly during pregnancy. A substantial increase in the clearance of drugs eliminated by renal mechanisms also has been noted. A significant number of women are clinically depressed during pregnancy and postpartum, and eliminating treatment for depression during pregnancy may have negative consequences for both mother and fetus. Among women with depression who are treated with selective serotonin reuptake inhibitors, the dose needed to maintain efficacy increases across the course of pregnancy. Drug disposition and response not only can differ between men and women, but also between pregnant and nonpregnant women. Research is needed to understand how pregnancy alters the pharmacokinetics and pharmacodynamics of drugs; then, efficacy trials can be initiated. Alternative strategies also need to be developed to characterize safety information.

A Report from the Pediatric Formulations Task Force: Perspectives on the State of Child-Friendly Oral Dosage Forms

Despite the fact that a significant percentage of the population is unable to swallow tablets and capsules, these dosage forms continue to be the default standard. These oral formulations fail many patients, especially children, because of large tablet or capsule size, poor palatability, and lack of correct dosage strength. The clinical result is often lack of adherence and therapeutic failure. The American Association of Pharmaceutical Scientists formed a Pediatric Formulations Task Force, consisting of members with various areas of expertise including pediatrics, formulation development, clinical pharmacology, and regulatory science, in order to identify pediatric, manufacturing, and regulatory issues and areas of needed research and regulatory guidance. Dosage form and palatability standards for all pediatric ages, relative bioavailability requirements, and small batch manufacturing capabilities and creation of a viable economic model were identified as particular needs. This assessment is considered an important first step for a task force seeking creative approaches to providing more appropriate oral formulations for children.

Dactinomycin and Vincristine Toxicity in the Treatment of Childhood Cancer: A Retrospective Study from the Children’s Oncology Group

Dactinomycin (AMD) and vincristine (VCR) have been used for the treatment of childhood cancer over the past 40 years but evidence‐based dosing guidance is lacking.

Special Challenges In Comparative Effectiveness Research On Children’s And Adolescents’ Health

The United States is undertaking a major expansion of comparative effectiveness research, with the potential to achieve systemwide improvements in health care quality, outcomes, and resource allocation. However, to achieve these improvements in childrens health and health care, comparative effectiveness research needs to be targeted, designed, conducted, and reported in ways that are responsive to the unique circumstances of children and adolescents. These include clinically important differences in the type and course of disease in children; demographic differences between the overall child and adult population in the United States, such as racial and ethnic makeup; and methodological issues involving study design. Our overarching point is that the base of evidence in pediatrics must not fall even further behind that for the adult population in an era of rapid advancement and funding of comparative effectiveness research.

Eunice Kennedy Shriver National Institute of Child Health and Human Development Pediatrics Formulation Initiative: Proceedings from the Second Workshop on Pediatric Formulations

BACKGROUND The Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH) organized a workshop held in November 2011 to address knowledge gaps that limit the availability of adequate pediatric formulations. This workshop was used as a means to identify the types of research innovations needed and to stimulate research efforts designed to improve the availability of pediatric formulations and the technologies required to make these formulations. METHODS Information for this article was gathered from the proceedings of the Second US PFI Workshop sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Maryland, on November 1 and 2, 2011, as well as from post-workshop discussions. The workshop preparation began with formation of 4 working groups: Biopharmaceutics, Biopharmaceutics Classification System (BCS), New Technology and Drug Delivery Systems, and Taste and Flavor. RESULTS The recommendations of the 4 working groups will form the basis for the development of a blueprint to guide future research efforts. The pediatric-specific problems identified include the heterogeneity of the population, the small size of the pediatric drug market, the limited number of new formulations for the large number of off-patent and unlabeled drugs, and the lack of universal agreement on how to define appropriate formulations for different ages and stages of development. There was consensus on the need to develop a universal technology platform for flexible pediatric dosage forms, transforming an empirical process into a science-based platform. A number of problems affect the availability of drugs in the developing world. Age-appropriate solid oral pediatric medicines for common diseases can have a global impact. Success on a global scale depends on the commitment of policy makers, regulators, scientists, pharmaceutical companies, sponsors, government, and research foundations to address gaps in knowledge and solve public health issues related to the availability of formulations in the developing world. CONCLUSIONS Solutions to the worldwide lack of appropriate pediatric formulations will require the development of a road map and the commitment of policy makers, regulators, scientists, pharmaceutical sponsors, academic institutions, governments, and research foundations. The development of a universal, cost-effective platform using existing or developing innovative technology that produces flexible pediatric dosage forms remains an important but elusive goal.

The National Institutes of Health and the Best Pharmaceuticals for Children Act

The majority of drugs used to treat children are not labeled for use in children. The Best Pharmaceuticals for Children Act of 2002, re-authorized as the US FDA Amendments Act of 2007, directs the National Institutes of Health (NIH) to sponsor pediatric clinical trials of drugs lacking patent protection, if the FDA request for studies has been declined. The NIH is currently sponsoring 17 clinical studies. Challenges encountered include a paucity of investigators who are trained in pediatric clinical pharmacology; inadequate knowledge of the mechanisms of drug action in a growing child; and lack of pediatric formulations.

Drug Studies in Newborns: A Therapeutic Imperative

Although some drugs have been developed for the neonate, drug development for the least mature and most vulnerable pediatric patients is lacking. Most of the drugs are off-label or off-patent and are empirically administered to newborns once efficacy has been demonstrated in adults and usefulness is suspected or demonstrated in the older pediatric population. Few drugs are approved by the Food and Drug Administration for use in this population. The factors that prevent the demonstration of efficacy and safety in the newborn are discussed and a change in the current approach for neonatal drug studies is suggested.

Meeting the Demand for Pediatric Clinical Trials

The bid for high-quality, cost-effective pediatric clinical trials requires robust research and regulatory playgrounds and an appropriately trained workforce. High-quality, cost-effective pediatric clinical trials require a robust research and regulatory infrastructure and a properly trained workforce.