Food And Drug Administration Requirements Research Articles

College of American Pathologists Proposal for the Oversight of Laboratory-Developed Tests

The US Food and Drug Administration (FDA) announced it will exercise authority over laboratory-developed tests (LDTs). Laboratory-developed tests have traditionally been developed and offered in laboratories as a service to patients and regulated under the Clinical Laboratory Improvement Amendments of 1988 (Clinical Laboratory Improvements Act). Laboratories now face potential dual regulatory oversight from both the Centers for Medicare and Medicaid Services (CMS) and the FDA. The College of American Pathologists (CAP) constructed a proposal to minimize redundancy of agency oversight and burden to laboratories. Modifications to the proposal continue while the laboratory community awaits release of the guidance documents that will stipulate FDA requirements. To describe the historical context framing the entry of FDA into the oversight of LDTs and outline the CAP LDT Proposal in its current form. PubMed review of published literature; United States Constitution; and online information resources from the National Institutes of Health, FDA, and US Government. The College of American Pathologists is a leader in laboratory quality and has unique insights into the benefits and risks to patients presented by LDTs. Continued dialog with officials from the FDA and CMS will promote public and private collaborative efforts to assure innovation of diagnostic testing, public information, and patient safety for clinical diagnostic testing.

Comparison of the quantitative performances and measurement uncertainty estimates obtained during method validation versus routine applications of a novel hydrophilic interaction chromatography method for the determination of cidofovir in human plasma

Method validation is essential to ensure that an analytical method is fit for its intended purpose. Additionally, it is advisable to estimate measurement uncertainty in order to allow a correct interpretation of the results generated by analytical methods. Measurement uncertainty can be efficiently estimated during method validation as a top–down approach. However, method validation predictions of the quantitative performances of the assay and estimations of measurement uncertainty may be far away from the real performances obtained during the routine application of this assay. In this work, the predictions of the quantitative performances and measurement uncertainty estimations obtained from a method validation are compared to those obtained during routine applications of a bioanalytical method. For that purpose, a new hydrophilic interaction chromatography (HILIC) method was used. This method was developed for the determination of cidofovir, an antiviral drug, in human plasma. Cidofovir (CDV) is a highly polar molecule presenting three ionizable functions. Therefore, it is an interesting candidate for determination by HILIC mode. CDV is an acyclic cytidine monophosphate analog that has a broad antiviral spectrum and is currently undergoing evaluation in clinical trials as a topical agent for treatment of papillomavirus infections. The analytical conditions were optimized by means of design of experiments approach in order to obtain robust analytical conditions. These ones were absolutely necessary to enable the comparisons mentioned above. After a sample clean-up by means of solid phase extraction, the chromatographic analysis was performed on bare silica stationary phase using a mixture of acetonitrile–ammonium hydrogen carbonate (pH 7.0; 20 mM) (72:28, v/v) as mobile phase. This newly developed bioanalytical method was then fully validated according to FDA (Food and Drug Administration) requirements using a total error approach that guaranteed that each future result will fall within acceptance limits of ±30% with a probability of 95% over a concentration range of 92.7–1020 ng/mL. A routine application of the cidofovir determination in two pre-clinical trials demonstrated that the prediction made during the pre-study validation was consistent by retrospective analysis of the quality control (QC) samples. Finally, comparison of the measurement uncertainty estimations calculated from the method validation with those obtained from the routine application of the method was performed, stressing that the estimations obtained during method validation underestimated those obtained from routine applications and that the magnitude of this underestimation was function of the cidofovir concentration. Finally, this new HILIC method is reliable, easily applicable to routine analysis and transposable at low cost in other laboratories.

Estrogen Activity in Plastic Products: Yang et al. Respond

Estrogen Activity in Plastic Products: Yang et al. Respond

Impact of the U.S. Food and Drug Administration Cardiovascular Assessment Requirements on the Development of Novel Antidiabetes Drugs

Lingering questions related to cardiovascular (CV) safety of type 2 diabetes treatments resulted in new U.S. Food and Drug Administration (FDA) regulations requiring careful assessment of CV risk. These new requirements will provide the medical community with robust data to estimate CV risk associated with new therapeutic agents. To meet these requirements, phase 2 and 3 development programs will need to be larger and more comprehensive and will include high-risk patients. In addition, it is likely that most (if not all) newly approved drugs will be required to conduct post-approval CV safety outcome studies. The purpose of this article is to review the drivers for the new FDA requirements and how these new requirements will affect the development of novel antidiabetes drugs. The goals of antidiabetes treatment are to forestall the metabolic effects of high glucose levels and to prevent microvascular and macrovascular complications. Compelling data in type 2 diabetic patients support the conclusion that improved long-term glycemic control reduces the risk of microvascular complications (1,2). Based on several large outcome studies (e.g., the Diabetes Control Complications Trial and the UK Prospective Diabetes Study [UKPDS]), glycosylated hemoglobin (HbA1c) was established as a surrogate biomarker of glycemic control and therapeutic goals were set accordingly (3). Cardiovascular disease is the leading cause of death in patients with type 2 diabetes; more than 60% die of CV disease, and an even greater proportion have serious CV-related complications. Diabetes is associated with a two- to fourfold increase in the risk of coronary heart disease and death (4). Patients with type 2 diabetes who have not had a myocardial infarction (MI) have a risk of infarction similar to that of nondiabetic patients who have had a prior MI (5–7). Pooled data from patients with acute coronary syndrome (ACS) in …

The Impact of Regulatory Compliance on Agile Software Processes with a Focus on the FDA Guidelines for Medical Device Software

The difficulty of complying with different regulations has become more evident as a large number of regulated businesses are mandated to follow an ever-increasing set of regulations. These regulations often drive significant changes in the way organizations operate to deliver value to their customers. This paper focuses on the impact of the Food and Drug Administration (FDA) regulations on agile software development processes, which in many ways can be considered as just another type of organizational processes. Particular focus is placed on the ability for Extreme Programming (XP) to support FDA requirements. Findings show that XP fails to meet many of the FDA guidelines for medical device software, which increases the risks of non-compliance for organizations that have adopted XP as their main software process. The results of this study can lead the work towards designing an extension to XP for FDA regulations.

Reaction to the recent publication by Rosemary Basson entitled ‘Testosterone therapy for reduced libido in women’

Reaction to the recent publication by Rosemary Basson entitled ‘Testosterone therapy for reduced libido in women’

Gender Bias in Studies for Food and Drug Administration Premarket Approval of Cardiovascular Devices

Cardiovascular devices can have different safety and effectiveness profiles in men and women. The type and quality of sex-specific data reviewed by the Food and Drug Administration (FDA) before approval of these devices are unknown. We performed a systematic review of the demographics, comments on gender bias, and analysis of results by sex for 78 high-risk cardiovascular devices that received premarket approval by the FDA between 2000 and 2007. FDA summaries of evidence did not report sex of enrollees in 34 (28%) of 123 studies. For studies reporting sex distribution, the study populations were, on average, 67% men. There was no increase in the enrollment of women over time. Explanations for the relatively low percentage of women often stated that the trials reflected either underlying disease distribution or referral rates for similar procedures or that the sex distribution reflected similar or previous trials. Forty-one percent of studies included a gender bias comment or analysis, and 12 (26%) of 47 of these analyses identified some difference in device safety or effectiveness by sex. There is a lack of sex-specific safety and effectiveness data for high-risk cardiovascular devices before FDA approval. The justifications for this lack of evidence may perpetuate the status quo. More rigorous FDA requirements for sex-specific data before device approval could present an opportunity to improve cardiovascular outcomes.

Bioavailability of Three Rufinamide Oral Suspensions Compared With the Marketed 400-mg Tablet Formulation: Results From a Randomized-Sequence, Open-Label, Four-Period, Four-Sequence Crossover Study in Healthy Subjects

BackgroundRufinamide is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients aged ≥4 years. ObjectivesThe primary purpose of this study was to compare the relative bioavailability and other pharmacokinetics of rufinamide administered as a 400-mg tablet formulation (reference) with 10 mL of a newly developed 40-mg/mL suspension (test) manufactured using 3 different homogenization speeds in healthy subjects under fed conditions. The study also explored whether homogenization speed had any effect on rufinamide pharmacokinetics when administered as a suspension formulation. MethodsThis was a randomized, open-label, crossover, single-dose study in healthy, fed subjects aged 18 to 55 years (inclusive), conducted at a single center in the United Kingdom. Subjects were randomized to 1 of 4 treatment sequences, with each sequence consisting of 4 treatment periods. In each treatment period, subjects received a single dose of either the reference product (400-mg rufinamide tablet) or the test product (10 mL of rufinamide suspension [40 mg/mL] manufactured using 3 different homogenization speeds [1800, 2100, and 3000 revolutions per minute (rpm)]). Serial blood samples were collected for 72 hours after dosing for the measurement of rufinamide in plasma. Primary comparisons between test (suspension) and reference (tablet) formulations focused on AUC from 0 to 72 hours (AUC0–72h) and Cmax. The formulations were considered bioequivalent if the ratios of geometric least squares means and associated 90% CIs of AUC0–72h and Cmax were within the predetermined range of 80%–125%, according to the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) requirements. Tolerability was assessed by subject interviews, physical examinations, and laboratory tests. ResultsTwenty-four healthy subjects were randomized: 8 were male and 16 were female; 22 white, 1 black, and 1 Asian subjects were enrolled. Mean (SD) age was 29.8 (10.0) years. Mean weight was 68.2 (11.0) kg, and mean body mass index was 23.6 (3.0) kg/m2. Twenty-one subjects completed the study; 2 subjects discontinued because of adverse events (both urinary tract infections considered unrelated to treatment) and 1 because of protocol deviation. The 72-hour pharmacokinetic data for the last complete treatment period before discontinuation were included in group means.The geometric least squares mean Cmax value for the reference tablet formulation was 4840.24 ng/mL; and 4254.87, 4204.29, and 4418.44 ng/mL for the 1800-, 2100-, and 3000-rpm test suspensions, respectively. The ratios of the geometric least squares mean values (test/reference) for Cmax were 0.88 (90% CI, 0.84–0.92), 0.87 (0.83–0.91) and 0.91 (0.88–0.95) for the 1800-, 2100-, and 3000-rpm suspensions, respectively, compared with the tablet formulation. The geometric least squares mean AUC0–72h values were 75,960.48 ng · h/mL for the tablet formulation and 74,279.02, 73,746.03, and 73,701.17 ng · h/mL for the 1800-, 2100-, and 3000-rpm suspensions, respectively. The ratios of the geometric least squares mean values (test/reference) for AUC0–72h were 0.98 (90% CI, 0.95–1.00), 0.97 (0.95–1.00) and 0.97 (0.95–0.99) for the 1800-, 2100-, and 3000-rpm suspensions, respectively, compared with the tablet formulation. The ratios and associated 90% CI limits (for test suspensions to the reference tablet) for AUC0–72h and Cmax were within the FDA and EMA criteria for assuming bioequivalence to the 400 mg tablet. Comparisons among the 3 rufinamide test suspensions also met the regulatory criteria for assuming bioequivalence to one another.Treatment-emergent adverse events (TEAEs) were experienced by 18.2% (4/22) of subjects treated with the 400-mg tablet, 21.7% (5/23) of subjects treated with the 1800-rpm suspension, 26.1% (6/23) of subjects treated with the 2100-rpm suspension, and 8.7% (2/23) of subjects treated with the 3000-rpm suspension. Overall, 54.2% (13/24) of subjects experienced a TEAE; all TEAEs were mild or moderate in severity, with headache being the most frequently reported (37.5% [9/24]). There were no serious adverse events or deaths. ConclusionThis single-dose study in a small population of fed, healthy subjects found no statistically significant differences in relative bioavailability among each of the 3 test suspensions and the currently marketed 400-mg tablet formulation of rufinamide, meeting FDA and EMA regulatory requirements for assuming bioequivalence.

U.S. FDA requirements for Human Vaccine Product Safety and Potency Testing

The Office of Vaccines Research and Review (OVRR) at the Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA) regulates preventative and therapeutic vaccines for infectious disease indications for use in humans. The framework for regulation of biological products includes Statutes (e.g. The U.S. Food, Drug and Cosmetic Act and the Public Health Service Act), regulations as defined in the Code of Federal Regulations (CFR) and guidance documents. Approval of a biologics license for a product, including vaccines, is based on a demonstration of safety, purity, and potency and assurance that the facility for manufacture, processing, and packaging meets standards to ensure that product released for distribution is safe, pure and potent. The regulatory definitions of safety, purity and potency are detailed in Title 21 of the Code of Federal regulations (CFR) Part 600. All manufacturing information including tests for safety, purity, and potency for a particular product must be documented in the Biologics License Application (BLA). Potency testing may be performed on the final bulk sample or final container sample and may consist of either in vivo or in vitro tests or both. To change a potency or safety test post-licensure requires a Supplement to the License and data to support a modified or alternative test. CBER encourages the development and use of appropriate alternative methods for vaccine safety and potency testing.

Use of patient-reported outcomes in medical product development: a report from the 2009 NEI/FDA Clinical Trial Endpoints Symposium.

On October 13, 2009, the third in a series of meetings to discuss endpoints in ophthalmic clinical trials was held at the National Institutes of Health (NIH). This event, about patient-reported outcomes (PROs), was an opportunity for the vision community and the U.S. Food and Drug Administration (FDA) to meet and discuss the FDA requirements for adding new endpoints to the evaluation of ophthalmic treatments and products. The meeting was attended by researchers, clinicians, policymakers, and representatives from industry and vision associations. The first two meetings, in 2006 and 2008, were held to discuss endpoints and clinical trial strategies for evaluating new treatments for age-related macular degeneration (AMD) and diabetic retinopathy and glaucoma treatments, respectively.1,2 The objectives of this conference were to provide definitions of PROs, to describe the importance of PROs, to assess what is known and what should be known about PROs in ophthalmology, to provide insights on how the FDA evaluates development and validation of PRO instruments, and to report on clinical trial design issues relevant to PROs. An ancillary issue was the use of PROs in labeling claims and patient-information materials. The meeting was organized by the Association for Research in Vision and Ophthalmology (ARVO) and co-chaired by Rohit Varma, MD, PhD, Frederick Ferris, MD, and Neil Bressler, MD. Representing the FDA were Laurie Burke, RPh, PhD, Wiley Chambers, MD, Malvina Eydelman, MD, Danica Marinac-Dabic, MD, PhD, and Paivi Miskala. All participants and their affiliations are shown in the box on page 6096). Growing evidence indicates the importance of vision-related PROs in clinical trials for evaluating medical drugs and devices, not only for medical product labeling, but also to expand the understanding of clinical trial outcomes.3–7 Although the FDA has incorporated labeling for PROs in areas outside of ophthalmology, the issues and challenges relevant to ophthalmology are just beginning to be understood. Most clinical trials in ophthalmology use visual acuity measured by an eye chart to assess changes in vision related to experimental conditions. However, as many clinicians and researchers are aware, objective measurement of visual acuity (and/or visual field) may not adequately describe the total impact of a treatment on a patient's visual world.

Discussion about traditional Chinese medicine pharmacokinetics study based on first botanical drug approved by FDA

Pharmacokinetics study is one of main components of pharmaceuticals development. Food and Drug Administration (FDA) approved Veregen as the first botanical drug in 2006. This article introduced FDA's requirement on pharmacokinetics study of botanical drug and pharmacokinetics studies of Veregen, summarized current requirement and status quo of pharmacokinetics study on traditional Chinese medicine (TCM) and natural medicine in China, and discussed about pharmacokinetics study strategy for TCM and natural medicine.

Lung Water

Newspaper headlines have greeted with circumspection the report from the Government Accountability Office on the United States Food and Drug Administration (FDA) processes to regulate medical devices. They used sentences such as “Left to the FDA’s own devices” 1 and “Is That Device Safe?” 2. Such headlines bring attention to the fact that FDA requirements for approval and clearance of medical devices are markedly different from those for drugs3, 4. Most new devices are cleared, not approved, through the premarket notification (510(k)) pathway. This is a FDA process based on the assumption that the majority of new devices are essentially equivalent to those already approved. Physiological monitors are usually among these, and frequently enter the market due to their substantial equivalence to previous models, with limited scrutiny of efficacy 3, 4. Thus, as new monitors are introduced, it is crucial for good clinical practice to understand their principles, advantages and limitations. In this issue of Anesthesiology, Easley et al.5 apply functional lung imaging techniques to study measurements of extravascular lung water (EVLW) using the single indicator (iced saline) transpulmonary thermodilution method. The device was recently cleared by the FDA (PiCCO, Pulsion Medical Systems, Munich, Germany).

Clinical-Trial System Said Ripe for Reform

Back to table of contents Previous article Next article Professional NewsFull AccessClinical-Trial System Said Ripe for ReformJun YanJun YanSearch for more papers by this authorPublished Online:5 Sep 2008https://doi.org/10.1176/pn.43.17.0006The Food and Drug Administration (FDA) is collaborating with Duke University researchers to find ways to improve the efficiency and quality of clinical trials.The Clinical Trial Transformation Initiative (CTTI), first announced in November 2007, is a public-private partnership hosted and coordinated by Duke University with participation from all areas of clinical research.The FDA has been criticized in recent years for inefficiency and lack of sufficient oversight. The number of new drug approvals, especially new compounds, has declined in recent years. In 2007, the FDA approved only 19 new drugs, the lowest since 1983, according to a Bloomberg/Arizona Daily Star report on January 10. Meanwhile, the cost of conducting a late-phase clinical trial can amount to tens of millions of dollars.Drug companies are increasingly conducting global clinical trials outside of the United States so that more patients can be enrolled at more sites simultaneously and more data can be obtained sooner to meet FDA requirements for new-drug review. However, global trials, including some conducted in Third World countries, increase the agency's difficulty in monitoring the quality of these trials.The CTTI partnership is intended “to develop new standards and identify new methods and technologies that improve safety, boost the quality of information derived from clinical trials, and make the research process more efficient,” according to its Web site.The CTTI “was set up by the FDA in response to growing frustration over the complexity in conducting clinical trials and the long time frames involved in completing them,” said Judith Kramer, M.D., executive director of the CTTI and an associate professor of medicine at Duke University School of Medicine. She told Psychiatric News that the CTTI has heard from many people directly involved in clinical trials who are frustrated by the inefficiencies in the system.The cost and time of conducting trials limit the number of clinical questions that can be answered. Industry-sponsored clinical trials tend to focus on data needed for regulatory approvals. Physicians often find themselves in a position of prescribing FDA-approved drugs“ off-label” without adequate clinical-trial data for diseases affecting a small patient population without an approved treatment.Fundamentally changing the existing framework, however, requires stakeholders from different fields with different perspectives to develop global solutions for these problems, Kramer emphasized. Although the CTTI is still in the planning and organizing stage, Kramer expressed optimism that it can achieve its goals: “We ... announced the executive committee in May that consists of FDA representatives in the drug and medical device divisions; a patient advocate; representatives from the pharmaceutical industry, biotechnology, device companies, and contract research organizations; academic researchers; an at-large representative from the Tufts Center for the Study of Drug Development; and a liaison from the National Institutes of Health.”Kramer explained that CTTI plans to solicit ideas and participation from a variety of members. “We already have 36 organizations that have committed to join CTTI,” she said. “So far our membership includes a broad cross-section of industry, contract research organizations, professional societies, academic institutions, investigators, trade organizations, even a law firm specializing in regulatory law, and a private investment company.”Among the current members are the American College of Neuropsychopharmacology and American College of Clinical Pharmacology.If successful the findings derived from the CTTI will lead to changes in not only industry-sponsored clinical trials but also in pure academic research. “The quality of clinical trials is important to not only new drug approvals but also for medical practice,” said Kramer.The FDA has committed personnel but provides no funding for the research and other activities in the CTTI. The projects are expected to be funded by membership fees, which are based on a tiered structure depending on the type of the organization or company.Additional information about the CTTI is posted at<trialstransformation.org>.▪ ISSUES NewArchived

A critical evaluation of regulatory guidance on patient reported outcomes (PROs) addressing the use of PRO measures and endpoints in clinical trials

9590 Background: PROs are frequently used within industry-sponsored clinical trials and phase III registration trials. Recently, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have produced draft PRO guidance. The aim of this study was to evaluate this regulatory guidance with reference to the current expert and literature evidence base on the use of PROs in cancer trials and existing QoL tools (EORTC QLQ C30 and LC13). Methods: We conducted a systematic evaluation of both FDA and EMEA guidance and undertook quantitative analyses of 47 leading world key cancer research organizations that provided a formal response to the FDA guidance. In addition, we evaluated grey literature, 25 websites, and consulted over 20 key opinion leaders. Finally, we undertook a systematic literature review (medline 1990–2007) to evaluate conformity between regulatory positions and the scientific literature. Results: In comparison with the EMEA, the FDA has a more prescriptive approach, requiring tools with robust conceptual frameworks and psychometric studies. Current state assessment, advocated by the FDA, was contradicted by 88% of 25 reviewers addressing this issue (p < 0.001). Most expert reviewers (79 % of 14 non-significant) challenged the EMEA’ s and FDA’ s views that a general QOL claim requires improvement in all domains. Minor modifications or translations triggering full re-validation, was not considered realistic by nearly all organizations (97% of 32 p < 0.0001). In addition, substantial disagreement with FDA and EMEA exists on the subject of blinding (100% of 17 p < 0.0001). However, the Minimum Important Difference (MID) is in general agreed with by organizations (86% of 28 p < 0.05). Limited literature exists to support the debatable issues of the PRO guidance. On the whole, existing instruments (e.g. EORTC QLQ-LC13, MDASI) appear to meet FDA and EMEA requirements sufficiently. Conclusions: The regulatory PRO guidance were appreciated by the research community. However, differences on philosophical and design topics are evident. While this guidance is already impacting on trial design, we hope our evaluation will encourage dialogue between all parties, bringing harmony to such positions. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca

Follow-Up Care Often Lacking In Depression Treatment

Follow-Up Care Often Lacking In Depression Treatment

Pediatric Research and Scholarship: Another Gordian Knot?

Peter J. Davis, MD Appearing in this issue of the journal are four clinical papers on the use of dexmedetomidine in children (1–4). Previous studies of the use of this drug in children have dealt with sedation in the intensive care unit (5), prevention of postoperative agitation associated with sevoflurane anesthesia (6,7), and sedation for noninvasive procedures (8–12). These articles also illustrate a number of subtle concerns that are relevant to drug development in children and the ethical principles that guide research in human subjects as proposed by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, and summarized in the Belmont Report. In a randomized study of 30 pediatric cardiac surgical patients anesthetized with isoflurane and undergoing cardiopulmonary bypass (CPB), Mukhtar et al. (1) evaluated the effects of a continuous dexmedetomidine infusion on patients’ underlying hemodynamics and neuroendocrine system compared with patients receiving a saline control infusion. The authors infused dexmedetomidine after anesthetic induction until the termination of CPB. Dexmedetomidine attenuated the increase in the neuroendocrine markers of stress caused by sternotomy and CPB. In addition, dexmedetomidine provided better intraoperative hemodynamic stability in children with congenital heart disease. The report focused on hemodynamic outcome and did not address how this drug affected tracheal extubation time, recovery, length of hospital stay, or long-term outcome. Thus, the reader is left to ponder whether the reduction in the cortisol and norepinephrine, markers of neuroendocrine response, affect outcome. Moreover, we do not know how to titrate dexmedetomidine or if the optimum dose was administered. Are there dexmedetomidine doserelated adverse effects in this population? Should the dose be altered at the start of CPB? What is the effect of the fluctuation in the patient’s temperature (37° to 25° and return) on plasma levels achieved using a standard infusion rate? Why was dexmedetomidine not continued until the end of surgery? Why did the dexmedetomidine infusion not allow for less anesthetic administration, as had been shown in an adult study (13)? Did dexmedetomidine improve hemodynamic stability after bypass? Although this study measured biochemical endpoints to assess stress response, can we infer that the effect of this drug will be as salutary as the effect of opioids in the mortality of children having surgery for congenital heart disease? These questions were not answered because the study was not funded, limiting the number of subjects and the resources available to the investigators. Had this study been funded by the pharmaceutical manufacturer, the authors could have enrolled more patients, perhaps included other study centers, assayed blood for dexmedetomidine concentrations, developed pharmacokinetic models of dexmedetomidine in this population, and performed a pharmacodynamic concentration-versus-response analysis. In a study of 60 children undergoing magnetic resonance imaging, From the Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina; Department of Anesthesia, Stanford University, Stanford, California; Department of Anesthesiology, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania. Accepted for publication March 22, 2006. Address correspondence and reprint requests to Peter J. Davis, MD, Professor of Anesthesia and Pediatrics Anesthesiologistin-Chief, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213. Address e-mail to davispj@anes.upmc.edu. Copyright © 2006 International Anesthesia Research Society DOI: 10.1213/01.ANE.0000220033.34889.CE

In vivo efficacy of an alcohol-based surgical hand disinfectant containing a synergistic combination of ethylhexylglycerin and preservatives

Alcohol-based surgical hand disinfectants are widely available in healthcare settings. Some currently marketed alcohol-based products use active concentrations of antimicrobials to achieve the required efficacy, raising the risk for exposure to potentially irritating levels of antimicrobials. This study compares the in vitro and in vivo efficacy of an alcohol-based surgical hand preparation containing 70% ethanol and preservative levels of chlorhexidine gluconate (CHG) and benzalkonium chloride (BZK) in synergistic combination with ethylhexylglycerin (Surgicept) with a surgical hand disinfectant containing 61% ethanol and 1% CHG (Avagard). The in vivo efficacy of Surgicept and Avagard was evaluated in volunteers using the Tentative Final Monograph method of the Food and Drug Administration (FDA), and their prolonged effect against transient pathogens was compared using a pig skin model. Surgicept exceeded the FDA requirements for surgical hand antiseptic with mean log(10) reductions of 2.36, 3.3 and 3.54 in resident flora 1 min after initial application, and showed a persistent effect with mean log(10) reductions of 2.23, 2.73 and 3.3, 6h post application on days 1, 2 and 5, respectively. Surgicept showed a superior prolonged effect against transient bacteria compared with Avagard. Surgicept (70% alcohol and preservative levels of CHG and BZK) may provide similar in vivo efficacy as Avagard (61% ethanol and 1% CHG).

Pathogen Reduction in Unpasteurized Apple Cider: Adding Cranberry Juice To Enhance the Lethality of Warm Hold and Freeze-Thaw Steps

U.S. Food and Drug Administration (FDA) regulations require processors of apple cider sold wholesale to use processing steps that ensure a 5-log reduction in numbers of the pertinent pathogen, generally considered to be Escherichia coli O157: H7. Current widely used validated pathogen-reduction steps are thermal pasteurization and UV light treatment. These techniques may be unaffordable or undesirable for some processors. This study investigated the cran-cider process, which is the addition of cranberry juice at a 15% (vol/vol) level, followed by warm hold (45°C for 2 h) and freeze-thaw steps (−20°C for 24 h, 5°C for 24 h). When enumeration procedures did not include injury repair, the cran-cider process achieved a ≥5-log reduction in numbers of E. coli O157:H7, Salmonella serovars, and Listeria monocytogenes. However, an injury-repair step was included in the pathogen enumeration procedure in confirmatory trials, and the resulting E. coli O157:H7 reductions of 3.5 to 4.2 log did not meet the FDA requirement. Consumer evaluation of apple cider subjected to the cran-cider process was favorable with a mean (n = 197) score of 5.8 on a seven-point hedonic scale (where 6 equals “like moderately”) and 89% of panelists giving the product a positive score of 5, 6, or 7. The cran-cider process provides a novel way to improve microbial safety of unpasteurized apple cider, but it does not meet FDA-mandated pathogen reductions for wholesalers. However, cider makers selling apple cider only at retail could use the process to improve the safety of their product, provided containers were labeled with the FDA-mandated consumer warning.

Nanotechnologists Seek Biological Niches

Biologists are embracing nanotechnology—the engineering and manipulating of entities in the 1 to 100 nm range—and are exploiting its potential to develop new therapeutics and diagnostics.

A unique water optional health care personnel handwash provides antimicrobial persistence and residual effects while decreasing the need for additional products

BackgroundThe Centers for Disease Control and Prevention (CDC) has published guidelines for hand hygiene practices, recommending a handwash regimen that alternates between waterless alcohol products and antimicrobial or nonantimicrobial soap and water. The advent of an alcohol-based product that can be used with or without water (ie, water optional) to decontaminate the hands while providing immediacy of kill and antimicrobial persistence could reduce the confusion associated with handwash guidelines. Such a product has been developed, is alcohol-based (61%), and zinc pyrithione (ZPT) preserved (61% alcohol-ZPT) and has proven to be fully compliant with the Food and Drug Administration (FDA) and CDC guidelines.MethodsFDA-required testing of the 61% alcohol-ZPT product for the health care personnel handwash indication was performed as outlined in the Tentative Final Monograph (TFM) for Health-Care Antiseptic Drug Products, employing waterless and water-aided product applications. It was next assessed for antimicrobial persistence and residual effects by comparing it, in separate waterless and water-aided applications, with commonly available handwashes containing various antimicrobials in a 5-day study employing 49 subjects, in which samples were collected immediately and at 4 hours and 8 hours postapplication. The skin conditioning properties of this formulation were investigated via appropriate methods.ResultsThe 61% alcohol-ZPT product easily produced >3.0 log10 reduction in the indicator strain (Serratia marcescens) following the first wash, exceeding the 2.0 log10 FDA requirement. This level of performance was maintained through the tenth wash, surpassing the 3.0 log10 FDA requirement for the handwash indication. For the assessment of persistence and residual effect in the waterless mode, the water-optional, 61% alcohol-ZPT product consistently produced log10 reductions of nearly 3.5 or greater at every point over the entire study period. In the water-aided configuration, similar results were obtained as log10 reductions of 2.5 were observed. The formulation is nonirritating, actually contributing to hand skin condition.ConclusionsThe 61% alcohol-ZPT product exceeds all FDA criteria for the health care personnel handwash indication and is a significant advancement in the concept of skin antisepsis. It represents a single product suitable for use in all hand hygiene settings, demonstrating improved antimicrobial persistence and residual effects. The 61% alcohol-ZPT formulation contributes positively to overall hand conditioning, and a previously reported study has documented it to be virucidal for several DNA and RNA viruses.