Safe lists for medications in pregnancy: inadequate evidence base and inconsistent guidance from Web-based information, 2011.

PURPOSE: Medication use during pregnancy is common and increasing. Women are also increasingly getting healthcare information from sources other than their physicians. METHODS: This report summarizes an environmental scan that identified 25 active Internet sites that list medications reported to be safe for use in pregnancy and highlights the inadequate evidence base and inconsistent guidance provided by these sites. RESULTS: These lists included 245 different products, of which 103 unique components had been previously evaluated in terms of fetal risk by the Teratogen Information System (TERIS), a resource that assesses risk of birth defects after exposure under usual conditions by consensus of clinical teratology experts. For 43 (42%) of the 103 components that were listed as 'safe' on one or more of the Internet sites surveyed, the TERIS experts were unable to determine the fetal risk based on published scientific literature. For 40 (93%) of these 43, either no data were available to assess human fetal risk or the available data were limited. CONCLUSIONS: Women who see a medication on one of these 'safe' lists would be led to believe that there is no increased risk of birth defects resulting from exposure. Thus, women are being reassured that fetal exposure to these medications is safe even though a sufficient evidence base to determine the relative safety or risk does not exist.

Pediatric cardiovascular safety: challenges in drug and device development and clinical application.

Development of pediatric medications and devices is complicated by differences in pediatric physiology and pathophysiology (both compared with adults and within the pediatric age range), small patient populations, and practical and ethical challenges to designing clinical trials. This article summarizes the discussions that occurred at a Cardiac Safety Research Consortium-sponsored Think Tank convened on December 10, 2010, where members from academia, industry, and regulatory agencies discussed important issues regarding pediatric cardiovascular safety of medications and cardiovascular devices. Pediatric drug and device development may use adult data but often requires additional preclinical and clinical testing to characterize effects on cardiac function and development. Challenges in preclinical trials include identifying appropriate animal models, clinically relevant efficacy end points, and methods to monitor cardiovascular safety. Pediatric clinical trials have different ethical concerns from adult trials, including consideration of the subjects' families. Clinical trial design in pediatrics should assess risks and benefits as well as incorporate input from families. Postmarketing surveillance, mandated by federal law, plays an important role in both drug and device safety assessment and becomes crucial in the pediatric population because of the limitations of premarketing pediatric studies. Solutions for this wide array of issues will require collaboration between academia, industry, and government as well as creativity in pediatric study design. Formation of various epidemiologic tools including registries to describe outcomes of pediatric cardiac disease and its treatment as well as cardiac effects of noncardiovascular medications, should inform preclinical and clinical development and improve benefit-risk assessments for the patients. The discussions in this article summarize areas of emerging consensus and other areas in which consensus remains elusive and provide suggestions for additional research to further our knowledge and understanding of this topic.

Monitoring for teratogenic signals: pregnancy registries and surveillance methods.

Pregnant women should have access to medications that have been adequately studied for use to facilitate evidence-based risk-benefit discussions with their health care providers. Pregnant women experience acute medical emergencies, have existing conditions that require continued medical treatment or may develop pregnancy-induced conditions, making drug use during pregnancy unavoidable. Drug labeling is the primary source of information about a drug's use. The safety and efficacy data found in the label is derived from well-controlled clinical trials conducted prior to a drug's approval. However, pregnant women are rarely enrolled in clinical trials unless a product is specifically indicated for a pregnancy-related condition. Consequently, information regarding a product's use during pregnancy is usually collected postapproval. Current data collection tools include pregnancy exposure registries, retrospective cohort studies, pregnancy surveillance programs, case-control studies, spontaneous reports of adverse events and case reports. Each tool has strengths and limitations in its ability to detect teratogenic signals. Combinations of different sources of data are necessary to acquire the most complete picture of potential teratogenic risk, as no single method can capture all desired data to help pregnant patients and women of child bearing potential make appropriate risk benefits decisions along with their health care providers.

Safety and transparency of pediatric drug trials.

OBJECTIVES: To quantify the frequency and type of new safety information arising from studies performed under the auspices of the Pediatric Exclusivity Program, to describe the dissemination of these findings in the peer-reviewed literature and compare this with the US Food and Drug Administration (FDA) review, and to describe their effect on pediatric labeling. DESIGN: Cohort study of the 365 trials performed for 153 drugs. SETTING: The Pediatric Exclusivity incentive from December 1997 through September 2007. PARTICIPANTS: Food and Drug Administration publicly available records and peer-reviewed literature retrievable by MEDLINE search. Main Exposures New safety findings obtained from the trials completed for exclusivity. OUTCOME MEASURES: Concordance of the information highlighted in the peer-reviewed article abstracts with the information in the FDA labeling and drug reviews. RESULTS: There were 137 labeling changes; we evaluated 129 of these (the 8 selective serotonin reuptake inhibitors were excluded from review). Thirty-three products (26%) had pediatric safety information added to the labeling. Of these, 12 products had neuropsychiatric safety findings and 21 had other important safety findings. Only 16 of 33 of these trials (48%) were reported in the peer-reviewed literature; however, 7 of 16 focused on findings substantively different from those highlighted in the FDA reviews and labeling changes. CONCLUSIONS: Medication adverse events in children often differ from those in adults, particularly those that are neuropsychiatric in nature. Labeling changes for pediatric use demonstrate that pediatric drug studies provide valuable and unique safety data that can guide the use of these drugs in children. Unfortunately, most of these articles are not published, and almost half of the published articles focus their attention away from the crucial safety data.

Drug therapy in pediatrics: a developing field.

For many years, drug therapies were not explicitly studied in the pediatric population. The lack of data forced clinicians to treat children using empiric therapy, often guessing at the treatment dose. In addition to the lack of dosing information, there was no evidence that a product would be safe and efficacious in this unique population. Because dermatologic conditions are common in children, this lack of information affected dermatologists. In 1998, a new legislation passed that encouraged drug development in pediatrics. Additional legislation followed that allowed the Food and Drug Administration the authority to require studies in pediatrics when it was anticipated that a product would be used in the pediatric population. With the new legislation and a better understanding of differences in the dose effectiveness and safety profiles of drugs in children when compared with adults, evidence-based treatment of pediatric patients is now possible.

Improving pediatric dosing through pediatric initiatives: what we have learned.

OBJECTIVE: The goal was to review the impact of pediatric drug studies, as measured by the improvement in pediatric dosing and other pertinent information captured in the drug labeling. METHODS: We reviewed the pediatric studies for 108 products submitted (July 1998 through October 2005) in response to a Food and Drug Administration written request for pediatric studies, and the subsequent labeling changes. We analyzed the dosing modifications and focused on drug clearance as an important parameter influencing pediatric dosing. RESULTS: The first 108 drugs with new or revised pediatric labeling changes had dosing changes or pharmacokinetic information (n = 23), new safety information (n = 34), information concerning lack of efficacy (n = 19), new pediatric formulations (n = 12), and extended age limits (n = 77). A product might have had > or = 1 labeling change. We selected specific examples (n = 16) that illustrate significant differences in pediatric pharmacokinetics. CONCLUSIONS: Critical changes in drug labeling for pediatric patients illustrate that unique pediatric dosing often is necessary, reflecting growth and maturational stages of pediatric patients. These changes provide evidence that pediatric dosing should not be determined by simply applying weight-based calculations to the adult dose. Drug clearance is highly variable in the pediatric population and is not readily predictable on the basis of adult information.

Peer-reviewed publication of clinical trials completed for pediatric exclusivity.

CONTEXT: Much of pediatric drug use is off-label because appropriate pediatric studies have not been conducted and the drugs have not been labeled by the US Food and Drug Administration (FDA) for use in children. In 1997, Congress authorized the FDA to grant extensions of marketing rights known as "pediatric exclusivity" if FDA-requested pediatric trials were conducted. As a result, there have been over 100 product labeling changes. The publication status of studies completed for pediatric exclusivity has not been evaluated. OBJECTIVE: To quantify the dissemination of results of studies conducted for pediatric exclusivity into the peer-review literature. DESIGN: Cohort study of all trials conducted for pediatric exclusivity between 1998 and 2004 as determined by MEDLINE and EMBASE searches through 2005, the subsequent labeling changes, and the publication of those studies in peer-reviewed journals. We categorized any labeling changes resulting from the studies as positive or negative for the drug under study. We then evaluated aspects of the studies and product label changes that were associated with subsequent publication in peer-reviewed medical journals. MAIN OUTCOME MEASURES: Publication of the trial data in peer-reviewed journals. RESULTS: Between 1998 and 2004, 253 studies were submitted to the FDA for pediatric exclusivity: 125 (50%) evaluated efficacy, 51 (20%) were multi-dose pharmacokinetic, 34 (13%) were single-dose pharmacokinetic, and 43 (17%) were safety studies. Labeling changes were positive for 127/253 (50%) of studies; only 113/253 (45%) were published. Efficacy studies and those with a positive labeling change were more likely to be published. CONCLUSIONS: The pediatric exclusivity program has been successful in encouraging drug studies in children. However, the dissemination of these results in the peer-reviewed literature is limited. Mechanisms to more widely disperse this information through publication warrant further evaluation.