Evaluation of ventricular arrhythmias in early clinical pharmacology trials and potential consequences for later development.

This white paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of ventricular arrhythmias in early clinical pharmacology trials and their potential consequences for later clinical drug development. Ventricular arrhythmias are infrequent but potentially important medical events whose occurrence in early clinical pharmacology trials can dramatically increase safety concerns. Given the increasing concern with all potential safety signals and the resultant more extensive electrocardiographic monitoring of subjects participating in early phase trials, an important question must be addressed: Are relatively more frequent observations of ventricular arrhythmias related simply to more extensive monitoring, or are they genuinely related to the drug under development? The discussions in this paper provide current thinking and suggestions for addressing this question.

Assessing proarrhythmic potential of drugs when optimal studies are infeasible.

Assessing the potential for a new drug to cause life-threatening arrhythmias is now an integral component of premarketing safety assessment. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline (ICH) E14 recommends the "Thorough QT Study" (TQT) to assess clinical QT risk. Such a study calls for careful evaluation of drug effects on the electrocardiographic QT interval at multiples of therapeutic exposure and with a positive control to confirm assay sensitivity. Yet for some drugs and diseases, elements of the TQT Study may be impractical or unethical. In these instances, alternative approaches to QT risk assessment must be considered. This article presents points to consider for evaluation of QT risk when alternative approaches are needed.

Increasing participation of women in early phase clinical trials approved by the FDA.

BACKGROUND: Historically women were excluded from participation in phase 1 clinical trials. The goal of this study was to determine the participation of women and evaluate if participation has increased over time. METHODS: Clinical trial data submitted to the FDA for New Molecular Entities (NMEs) for adult, non-sex specific indications between January 2006 and December 2007 were reviewed. Electronic data available on phase 1 trial were evaluated for proposed indications, sex of participants, and doses tested. Therapeutic doses were obtained from the approved labeling. RESULTS: FDA approved 34 NMEs in 2006-2007. Data for 352 phase 1 trial of 30 NMEs were obtained. Data for 1 NME was not available electronically , 2 did not include new phase 1 data, and 1 provided only summary demographic data. All NMEs reviewed were for drugs used to treat conditions occurring in both men and women. Overall 120 (34.1%) trials had only male participants while 232 (65.9%) trials also enrolled female participants. 30.6% (3106/10,134) of participants were women. 149/352 (42.3%) of trials included safety and tolerability testing above the highest approved dose. In those trials, 32.5% (1628/5011) of the participants were women. An evaluation of trial start date illustrated the number of trials that enrolled women (p = 0.01) and the number of female participants (p < 0.001) has increased over time. CONCLUSION: Females subjects have traditionally been underrepresented in phase 1 trials. The number trials enrolling women and the number of women participating in phase 1 trials has increased since 2001, however, women are still underrepresented.

The Food and Drug Administration Office of Women's Health: impact of science on regulatory policy.

In 1994, the Food and Drug Administration Office of Women's Health (FDA-OWH) was created to provide leadership and policy direction for the Agency regarding issues of women's health. Within its first year, the FDA-OWH established a science program for women's health research, promoting the development of sound policy and regulation. In a little over a decade, the program has provided approximately 14 million dollars to fund more than 100 women's health research studies covering a broad range of health topics affecting women across their lifespan. Some studies, such as those elucidating drug effects on QT prolongation in women and drug-dietary supplement interaction, have had significant influence on regulatory decisions. Other studies have provided sound scientific data on sex and gender differences supporting FDA guidelines to protect women's health. This paper describes the science program at the FDA-OWH, providing examples of how funded research impacts regulatory policy.

Drug eluting stents and the critical path initiative: Evolving paradigms for safety evaluation.

Recent discussions between FDA and other stakeholders have focused on the benefits and risks associated with drug eluting stents (DES). A particular topic of focus is DES thrombosis, a rare, but serious, clinical event that may occur months to years after the initial implantation. FDA continues vigilant postmarket surveillance of DES currently on the market and is working with stent manufactures to ensure that new DES platforms in the development pipeline are safe and effective. FDA is also taking steps, under its Critical Path Initiative (CPI) [FDA. Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products, March 2004.http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html], to help address current and future DES safety issues. This article describes some of these activities.:

Antibiotic use in pregnancy and lactation: what is and is not known about teratogenic and toxic risks.

OBJECTIVE: Over ten million women are either pregnant or lactating in the United States at any time. The risks of medication use for these women are unique. In addition to normal physiologic changes that alter the pharmacokinetics of drugs, there is the concern of possible teratogenic and toxic effects on the developing fetus and newborn. This article reviews the risks and pharmacokinetic considerations for 11 broad-spectrum antibiotics that can be used to treat routine and life-threatening infections during pregnancy and lactation. DATA SOURCES: Information from the U.S. Food and Drug Administration (FDA) product labels, the Teratogen Information Service, REPROTOX, Shepard's Catalog of Teratogenic Agents, Clinical Pharmacology, and the peer-reviewed medical literature was reviewed concerning the use of 11 antibiotics in pregnant and lactating women. The PubMed search engine was used with the search terms "[antibiotic name] and pregnancy," "[antibiotic name] and lactation," and "[antibiotic name] and breastfeeding" from January 1940 to November 2005, as well as standard reference tracing. METHODS OF STUDY SELECTION: One hundred twenty-four references had sufficient information concerning numbers of subjects, methods, and findings to be included. TABULATION, INTEGRATION, AND RESULTS: The teratogenic potential in humans ranged from "none" (penicillin G and VK) to "unlikely" (amoxicillin, chloramphenicol, ciprofloxacin, doxycycline, levofloxacin, and rifampin) to "undetermined" (clindamycin, gentamicin, and vancomycin). Assessments were based on "good data" (penicillin G and VK), "fair data" (amoxicillin, chloramphenicol, ciprofloxacin, doxycycline, levofloxacin, and rifampin), "limited data" (clindamycin and gentamicin), and "very limited data" (vancomycin). Significant pharmacokinetic changes occurred during pregnancy for the penicillins, fluoroquinolones and gentamicin, indicating that dosage adjustments for these drugs may be necessary. With the exception of chloramphenicol, all of these antibiotics are considered compatible with breastfeeding. CONCLUSION: Health care professionals should consider the teratogenic and toxic risk profiles of antibiotics to assist in making prescribing decisions for pregnant and lactating women. These may become especially important if anti-infective countermeasures are required to protect the health, safety, and survival of individuals exposed to pathogenic bacteriologic agents that may occur from bioterrorist acts.

Thalidomide use in the US : experience with pregnancy testing in the S.T.E.P.S. programme.

INTRODUCTION: In 1998, thalidomide (Thalomid), a known human teratogen, was approved by the US FDA for the treatment of erythema nodosum leprosum. To prevent fetal exposure to thalidomide, a restricted distribution risk management programme, the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.), was implemented. All clinicians, pharmacists and patients who prescribe, dispense and receive thalidomide, respectively, are required to enroll in S.T.E.P.S. Sexually active females of childbearing potential must use two methods of birth control before, during and after treatment. These patients must also have a negative pregnancy test within 24 hours before beginning therapy and periodically while on therapy. The objective of this report is to summarise the patterns of thalidomide use and to describe the occurrence of positive pregnancy tests in females of childbearing potential while they were using thalidomide in the S.T.E.P.S. programme in the US. STUDY DESIGN/METHODS: A retrospective review of patients receiving thalidomide within the S.T.E.P.S. programme from September 1998 to 31 December 2004 to determine the occurrence of positive pregnancy tests whilst on treatment. RESULTS: Approximately 124,000 (43% female) patients were registered within the S.T.E.P.S. programme between September 1998 and 31 December 2004. Approximately 6,000 patients were females of childbearing potential, representing 5% of all patients and 11% of all female patients. Between 30 July 2001 and 31 December 2004, >88% of thalidomide use was for oncological conditions. There were 72 females of childbearing potential who had positive pregnancy tests. Sixty-nine of these patients had false positive pregnancy tests. Of the remaining three, one woman was pregnant while on thalidomide. This patient had an initial negative test and received thalidomide. Therapy was stopped when she had a positive pregnancy test. This pregnancy resulted in a miscarriage. Two additional patients were determined to be pregnant before receiving thalidomide. CONCLUSIONS: The S.T.E.P.S. programme is critical to managing the risks of thalidomide-associated teratogenicity. Sustained vigilance among health care providers and patients receiving thalidomide is essential to its continued success. Health care providers should be aware of the occurrence of false-positive pregnancy tests in females of childbearing potential receiving thalidomide.

Randomized, controlled, double-blind trial of daily oral azithromycin in adults for the prophylaxis of Plasmodium vivax malaria in Western Thailand.

We assessed the prophylactic efficacy of azithromycin (250 mg/day) against malaria in 276 adults in western Thailand in a randomized, double-blind, placebo-controlled trial. After antimalarial suppressive treatment, volunteers were randomized in a 2:1 ratio to either the azithromycin or placebo, respectively. Study medication was given for an average of 74 days. The azithromycin group (n = 179) had five endpoint parasitemias (1 Plasmodium vivax and 4 P. falciparum), and the placebo group (n = 97) had 28 endpoint parasitemias (21 P. vivax, 5 P. falciparum, and 2 mixed infections). Adverse events and compliance and withdrawal rates were similar in both groups. The protective efficacy (PE) of azithromycin was 98% for P. vivax (95% confidence interval [CI] = 88-100%). There were too few cases to reliably estimate the efficacy of azithromycin for P. falciparum (PE =71%, 95% C =-14-94%). We conclude that daily azithromycin was safe, well-tolerated, and had a high efficacy for the prevention of P. vivax malaria.

Human milk biomonitoring data: interpretation and risk assessment issues.

Biomonitoring data can, under certain conditions, be used to describe potential risks to human health (for example, blood lead levels used to determine children's neurodevelopmental risk). At present, there are very few chemical exposures at low levels for which sufficient data exist to state with confidence the link between levels of environmental chemicals in a person's body and his or her risk of adverse health effects. Human milk biomonitoring presents additional complications. Human milk can be used to obtain information on both the levels of environmental chemicals in the mother and her infant's exposure to an environmental chemical. However, in terms of the health of the mother, there are little to no extant data that can be used to link levels of most environmental chemicals in human milk to a particular health outcome in the mother. This is because, traditionally, risks are estimated based on dose, rather than on levels of environmental chemicals in the body, and the relationship between dose and human tissue levels is complex. On the other hand, for the infant, some information on dose is available because the infant is exposed to environmental chemicals in milk as a "dose" from which risk estimates can be derived. However, the traditional risk assessment approach is not designed to consider the benefits to the infant associated with breastfeeding and is complicated by the relatively short-term exposures to the infant from breastfeeding. A further complexity derives from the addition of in utero exposures, which complicates interpretation of epidemiological research on health outcomes of breastfeeding infants. Thus, the concept of "risk assessment" as it applies to human milk biomonitoring is not straightforward, and methodologies for undertaking this type of assessment have not yet been fully developed. This article describes the deliberations of the panel convened for the Technical Workshop on Human Milk Surveillance and Biomonitoring for Environmental Chemicals in the United States, held at the Hershey Medical Center, Pennsylvania State College of Medicine, on several issues related to risk assessment and human milk biomonitoring. Discussion of these topics and the thoughts and conclusions of the panel are described in this article.

Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications.

CONTEXT: A neonatal behavioral syndrome linked to in utero serotonin reuptake inhibitor (SRI) exposure during the last trimester of pregnancy has been identified. The US Food and Drug Administration (FDA) and drug manufacturers have recently agreed to a class labeling change for SRIs, which include selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), to include information about potential adverse events in neonates exposed in utero. Integration of data about the neonatal behavioral syndrome into the management of pregnancy in women who take SRIs is a current challenge for physicians. OBJECTIVES: To review evidence regarding the SRI-related neonatal syndrome and to help clinicians guide their patients in a risk-benefit decision-making process. DATA SOURCES: We searched MEDLINE (1966-February 2005) and PsycINFO (1974-February 2005). All articles related to neonatal signs after in utero SRI exposure were acquired, as well as unpublished data on this topic from the FDA advisory committee meeting of June 2004. References cited in case reports and studies were reviewed. Foreign-language literature was included and translated to English. STUDY SELECTION AND DATA EXTRACTION: Studies were included if they had clearly identified maternal SRI exposure for a minimum of the final trimester of pregnancy through delivery and assessed neonatal outcomes. We identified 13 case reports describing a total of 18 cases. Nine cohort studies met criteria. When not included in the published article, relative risks and 95% confidence intervals (CIs) were computed from raw data and summary risk ratios and 95% CIs were determined with Mantel-Haenszel estimates. DATA SYNTHESIS: Compared with early gestational SRI exposure or no exposure, late SRI exposure carries an overall risk ratio of 3.0 (95% CI, 2.0-4.4) for a neonatal behavioral syndrome. The most SRI-related neonatal case reports involved fluoxetine and paroxetine exposures. Neonates primarily display central nervous system, motor, respiratory, and gastrointestinal signs that are usually mild and disappear by 2 weeks of age. Medical management has consisted primarily of supportive care in special care nurseries. A severe syndrome that consists of seizures, dehydration, excessive weight loss, hyperpyrexia, or intubation is rare in term infants (1/313 quantifiable cases). There have been no reported neonatal deaths attributable to neonatal SRI exposure. CONCLUSIONS: Available evidence indicates that in utero exposure to SRIs during the last trimester through delivery may result in a self-limited neonatal behavioral syndrome that can be managed with supportive care. The risks and benefits of discontinuing an SRI during pregnancy need to be carefully weighed for each individual patient. Development and validation of assessment methods and clinical management strategies are critical to advancing this research.

Pregnancy exposure registries.

Scientifically valid data on the safety of drug use during pregnancy are a significant public health need. Data are rarely available on the fetal effects of in utero exposure in human pregnancies, particularly when a drug is first marketed. Data from animal reproductive toxicology studies, which function as a screen for potential human teratogenicity, are usually all that is available in a product's labelling. For practising clinicians, translating known animal risks into an accurate assessment of teratogenic risks in their patients is very difficult, if not impossible. Without human data on the effects of in utero drug exposure, it is difficult for physicians and other healthcare providers (e.g. genetic counsellors) to adequately counsel patients about fetal risks. Therefore, a pregnant woman may decide to unnecessarily terminate a wanted pregnancy or forego needed drug therapy. In spite of the lack of data on the safety of drug use during human pregnancies, pregnant women are exposed to drugs either as prescribed therapy or inadvertently before pregnancy is known (over one-half of pregnancies are unplanned). Because little is known about the teratogenic potential of a drug in humans before marketing, post-marketing surveillance of drug use in pregnancy is critical to the detection of drug-induced fetal effects. The existing passive mechanism of spontaneous reporting of adverse drug effects is inadequate to routinely detect drug-induced fetal risks or lack of such risks. Therefore, post-marketing pregnancy exposure registries are being increasingly used to proactively monitor for major fetal effects and to describe margins of safety associated with drug exposure during pregnancy. However, differing methodological rigour has been applied to the development of pregnancy exposure registries. It is important that all pregnancy registries develop epidemiologically sound written study protocols a priori. It is only through the use of rigorous methodology and procedures that data from pregnancy exposure registries will withstand scientific scrutiny. Successful recruitment of an adequate number of exposed pregnancies, aggressive follow-up, and complete and accurate ascertainment of pregnancy outcome are critical attributes of a well-designed registry.

Risk management strategies in the Physicians' Desk Reference product labels for pregnancy category X drugs.

BACKGROUND: Drugs that carry a concern for teratogenicity are often classified as pregnancy category X in the drug label and contraindicated for use during pregnancy. Many drug labels can be found in the Physicians' Desk Reference (PDR), a widely used source of drug information by American clinicians and patients. OBJECTIVE: To review product labelling in the electronic PDR for the pregnancy category X products for pregnancy prevention risk management components in labelling. METHODS: The electronic version of the 2001 and 2002 PDR was searched for 'pregnancy category X' products using the full text search feature. All product labels identified were retrieved and reviewed for trade name, generic name, manufacturer and indication. Product labels were manually searched for any pregnancy prevention risk management strategies included in labelling. Those labels that had specific pregnancy prevention risk management strategies were further evaluated. RESULTS: One hundred and seventeen pregnancy category X products were obtained from 2249 products searched in the 2001 PDR database and 124 pregnancy category X products were obtained from the 2150 products in the 2002 PDR database. All pregnancy category X products identified were drug products. The label/package insert for each drug was reviewed to identify risk management strategies for pregnancy prevention. The majority of the labels include as the sole risk management strategy either a black box warning and/or a contraindication for use in women who are or may become pregnant. Only 13 drugs contained specific pregnancy prevention risk management strategies in the label directing the clinician and/or patient, e.g. frequency of pregnancy testing, number and type of contraception methods. Two drugs, bexarotene capsules and gel, were only included in the 2001 PDR. Three drugs, isotretinoin, acitretin, and thalidomide, have formal pregnancy prevention risk management programmes. CONCLUSION: This study demonstrates the varied risk management approaches in labelling for pregnancy prevention for pregnancy category X drugs. There is a need for consistency in the classification of pregnancy category X products and the pregnancy prevention risk management strategies utilised in the labelling for them.

Advanced science education in the regulatory arena: the Center for Drug Evaluation and Research Experience at the Food and Drug Administration.

A challenge faced by the Center for Drug Evaluation and Research (CDER) in effectively carrying out its mission requires it to integrate the disciplines of science, medicine, law, and public policy. One way to do that is by ensuring a highly trained multidisciplinary staff. The CDER has been able to meet this requirement by identifying the core competencies needed to accomplish its mission. The use of a competency-based training model in the planning, development, and delivery of its advanced scientific education program allows CDER staff to maintain current knowledge as well as prepare for future scientific education needs. The CDER educational model could be readily adapted to meet the educational needs of other organizations.

Development of performance matrix for generic product equivalence of acyclovir topical creams.

The effect of process variability on physicochemical characteristics and in vitro performance of qualitatively (Q1) and quantitatively (Q2) equivalent generic acyclovir topical dermatological creams was investigated to develop a matrix of standards for determining their in vitro bioequivalence with reference listed drug (RLD) product (Zovirax®). A fractional factorial design of experiment (DOE) with triplicate center point was used to create 11 acyclovir cream formulations with manufacturing variables such as pH of aqueous phase, emulsification time, homogenization speed, and emulsification temperature. Three more formulations (F-12-F-14) with drug particle size representing RLD were also prepared where the pH of the final product was adjusted. The formulations were subjected to physicochemical characterization (drug particle size, spreadability, viscosity, pH, and drug concentration in aqueous phase) and in vitro drug release studies against RLD. The results demonstrated that DOE formulations were structurally and functionally (e.g., drug release) similar (Q3) to RLD. Moreover, in vitro drug permeation studies showed that extent of drug bioavailability/retention in human epidermis from F-12-F-14 were similar to RLD, although differed in rate of permeation. The results suggested generic acyclovir creams can be manufactured to obtain identical performance as that of RLD with Q1/Q2/Q3.