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.

Adverse effects in women: implications for drug development and regulatory policies.

The requirement to establish safety of drugs prior to marketing has been in place since 1938 by the US Food, Drug and Cosmetic Act and is by no means a new concept. The efficacy regulations were enacted in 1962 via the Kefauver-Harris Amendment and the drug approval process has evolved thereafter. The assessment of safety and efficacy of drug products is made by pharmaceutical companies during drug development, which then goes through a regulatory review by the US FDA for the determination of market approval or nonapproval. The drug development and regulatory approval processes have endured close ongoing scrutiny by regulatory bodies, the public, US Congress and academic and private organizations and, as a result, have ensured continual refinement. Over the years, evidence has been emerging on varied drug responses in subgroup populations, and the underlying biology associated with age, race and sex as demographic variables have been examined. The resulting growing knowledge of disease burden, treatment response and disparate outcomes has generated opportunities to streamline and improve treatment outcomes in these populations. This article discusses the historical context of women's participation in clinical drug trials submitted to the FDA for regulatory review and approval purposes. The inadvertent consequences of women's exclusion or inadequate representation in past clinical trials and the evidentiary basis for understanding sex differences are also evaluated. Advances in the US regulatory processes to address treatment outcomes that are tied to the topic of this paper, specifically, adverse drug effects in women, are also discussed.

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.:

Risk minimization practices for pregnancy prevention: understanding risk, selecting tools.

According to the March of Dimes, approximately 4% (1/28) of babies are born in the US each year with a birth defect. For the majority of birth defects the etiology is unknown, although chemicals, including drug exposures, probably account for less than 1% of all birth defects. The identification of potential human teratogenicity during drug development is important because drug-induced adverse fetal effects are potentially preventable with the application of risk assessment strategies and risk minimization tools and programs to minimize risk of pregnancy exposure while preserving access to drug benefits; risk assessment and risk minimization together comprise risk management. It is important that risk minimization programs intended to limit fetal exposure use a consistent approach and are tailored to the product-specific risk concerns in order to optimize the benefit-risk balance for a particular drug. This paper highlights general considerations in developing specific risk minimization programs to prevent fetal drug exposure including the relative advantages and disadvantages of each strategy.

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.