Food And Drug Administration Guidance Research Articles

The US Food and Drug Administration Provides a Pathway for Licensing Vaccines for Global Diseases

Responding to an urgency for new vaccines for global diseases, in September 2008 the Center for Biologics Evaluation and Research (CBER) at the US Food and Drug Administration (FDA) published an important FDA Guidance Document (see Box 1), ‘‘General Principles for the Development of Vaccines to Protect Against Global Infectious Diseases,’’ [1] that should expand the FDA’s role in facilitating the development of new vaccines for global bacterial, viral, and parasitic diseases affecting millions of people in developing countries worldwide. In part, this action is in response to a changing paradigm in advocacy for global diseases and recognition on the part of developed nations that the facilitation of vaccines and other products for neglected diseases disproportionately affecting those living in poverty is an effort that benefits industrialized as well as low-income countries. Moreover, through the effort of researchers, the pharmaceutical and biotechnology industries, and guided by nongovernmental product development partnerships, many funded by the Bill & Melinda Gates Foundation, preventative vaccines for global diseases are becoming a reality. Recent progress in this area is exemplified by both a meningococcal vaccine [2] and a new malaria vaccine moving forward into phase III efficacy trials in several African nations [3] and by several candidate vaccines for the prevention of tuberculosis being tested in phase I and II trials [4]. Vaccines and therapeutics for other viral [5], bacterial [6], and parasitic [7] neglected diseases are also in various stages of progress. As these new products enter into clinical trials, it has become clear to product development partners that it is critically important to identify regulatory pathways leading to the timely evaluation and acceptance of safe and effective life-saving interventions. However, this effort is impeded by the fact that regulatory agencies in developing countries where tropical diseases are endemic often lack the capacity to review applications for new vaccines, resulting in lengthy delays in obtaining permission to conduct clinical trials. Better-resourced regulatory agencies such as the US FDA, Health Canada, and the European Union’s European Medicines Agency (EMEA) have been willing to help strengthen regulatory authorities in developing countries, mostly through capacity-building and training programs coordinated by the World Health Organization (WHO), yet their ability to license new vaccines for global diseases has been restricted by the paucity of these diseases within their countries [8]. Some new approaches are being undertaken by the EMEA and by WHO and are briefly described here. In 2004 the European Union introduced a resolution (Article 58) stating that the EMEA could provide a scientific opinion equivalent to a marketing authorization in cooperation with WHO for the evaluation of medicinal products intended

FIP Position Paper on Qualification of Paddle and Basket Dissolution Apparatus

The qualification process for ensuring that a paddle or basket apparatus is suitable for its intended use is a highly debated and controversial topic. Different instrument qualification and suitability methods have been proposed by the pharmacopeias and regulatory bodies. In an effort to internationally harmonize dissolution apparatus suitability requirements, the International Pharmaceutical Federation's (FIP) Dissolution/Drug Release Special Interest Group (SIG) reviewed current instrument suitability requirements listed in the US, European, and Japanese pharmacopeias and the International Conference on Harmonization (ICH) Topic Q4B on harmonization of pharmacopoeial methods, in its Annex 7, Dissolution Test General. In addition, the SIG reviewed the Food and Drug Administration (FDA) Draft Guidance for Industry, "The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2-Current Good Manufacturing Practice (CGMP)" and the related ASTM Standard E2503-07. Based on this review and several in-depth discussions, the FIP Dissolution/Drug Release SIG recommends that the qualification of a dissolution test instrument should be performed following the calibration requirements as indicated in the FDA (draft) guidance. If additional system performance information is desired, a performance verification test using US Pharmacopeia Reference Standard tablet or an established in-house reference product can be conducted. Any strict requirement on the use of a specific performance verification test tablet is not recommended at this time.

Indoor tanning injuries: an evaluation of FDA adverse event reporting data

In 1979 the Food and Drug Administration (FDA) designated indoor tanning units would be regulated medical devices and that each must have an exposure timer. In 1985 FDA added a scheduled series of doses designed to allow tanning with little risk of concomitant sunburn. Subsequently FDA/CDRH maintained databases in which medical device associated injuries were reported. The databases, MAUDE and its predecessor MDR, are available online. While these records, in part, are not intended for evaluation of adverse event rates, analysis provides insight into the etiology of UV-related tanning injuries. We compiled 142 records reported for 1985-2006 including 22% noninjury malfunctions. Of the reported injuries approximately 50% resulted from UV exposure, an average of <1/year resulted in hospitalization. At least 36% of the UV-related injuries were attributable to various (user/operator) noncompliance with FDA sunlamp guidance policies. During 1985-1995 there were six times more UV injuries than 1996-2006, presumably reflecting cessation of much mandatory reporting in 1996. Injury reports declined steady from 1997 to 2006. FDA guidance appears most efficacious in injury prevention and we encourage its incorporation into the enforceable performance standard. We also advise that tanning industry professional training programs seek standardization/accreditation of their personnel certifications through recognized accreditation bodies such as ANSI or ISO/IEC.

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FIP Position Paper on Qualification of Paddle and Basket Dissolution Apparatus

The qualification process for ensuring that a paddle or basket apparatus is suitable for its intended use is a highly debated and controversial topic. Different instrument qualification and suitability methods have been proposed by the pharmacopeias and regulatory bodies. In an effort to internationally harmonize dissolution apparatus suitability requirements, the International Pharmaceutical Federation's (FIP) Dissolution/Drug Release Special Interest Group (SIG) reviewed current instrument suitability requirements listed in the US, European, and Japanese pharmacopeias and the International Conference on Harmonization (ICH) Topic Q4B on harmonization of pharmacopoeial methods, in its Annex 7, Dissolution Test General. In addition, the SIG reviewed the Food and Drug Administration (FDA) Draft Guidance for Industry, “The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2—Current Good Manufacturing Practice (CGMP)” and the related ASTM Standard E2503-07. Based on this review and several in-depth discussions, the FIP Dissolution/Drug Release SIG recommends that the qualification of a dissolution test instrument should be performed following the calibration requirements as indicated in the FDA (draft) guidance. If additional system performance information is desired, a performance verification test using US Pharmacopeia Reference Standard tablet or an established in-house reference product can be conducted. Any strict requirement on the use of a specific performance verification test tablet is not recommended at this time.

Executive summary: workshop on issues in the design and conduct of clinical trials of antibacterial drugs in the treatment of community-acquired pneumonia.

Executive summary: workshop on issues in the design and conduct of clinical trials of antibacterial drugs in the treatment of community-acquired pneumonia.

Patient-reported outcomes: Assessment and current perspectives of the guidelines of the Food and Drug Administration and the reflection paper of the European Medicines Agency

AimsPatient-reported outcomes (PROs) have recently gained greater credibility with regulatory bodies aiming to standardise their use and interpretation in RCTs, thereby supporting medicinal product submissions. For this reason, the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have released guidelines. This review paper provides an overview of the current perspectives and views on these guidelines. MethodTo evaluate the FDA and EMEA PRO guidelines, 47 expert responses to the FDA guidance were qualitatively reviewed. Two reviewers independently extracted data from these letters and checked these responses to warrant consistency and agreement in the evaluation process. A PubMed literature review was systematically examined to obtain supporting evidence or related articles for both the guidance documents. ResultsGenerally, there is agreement between regulatory authorities and the research community on the contents of the FDA and EMEA PRO draft guidance. However, disagreements exist on significant philosophical topics (e.g. the FDA focuses more on conceptual models and symptoms than the EMEA) and design topics (e.g. the FDA is more restrictive on issues of recall bias, blinding of oncology trials and degrees of psychometric validation than researchers and the EMEA). This could influence the approval of PRO claims. ConclusionPRO guidance from the EMEA and FDA has been valuable, and has raised the profile and active debate of PROs in oncology. However, our review of the current opinion shows that there are controversial aspects of the guidance. Consequently, greater latitude should be given to how the guidance is interpreted and applied.

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

FDA Guidance on Off-Label Promotion and the State of the Literature From Sponsors

ALTHOUGH THE US FOOD AND DRUG ADMINISTRAtion (FDA) reviews and approves drugs for specific indications, the approval does not usually limit the use of those drugs in clinical practice. Indeed, prescribing for indications not reviewed by the FDA (“off-label”) is common. In a recent study of 160 frequently prescribed drugs, off-label use represented 21% of drug mentions, and 73% of these off-label uses had little or no scientific support. Off-label use has long been controversial because large numbers of patients may receive drugs that have had only limited testing for efficacy and safety, and some off-label uses may eventually be shown to have an unfavorable risk-benefit profile. High-profile examples include the use of the combination of fenfluramine and phentermine by millions of persons for weight loss and the widespread use of hormone therapy by postmenopausal women to prevent coronary artery disease. Although the FDA does not restrict physician prescribing for off-label indications, it does regulate the manufacturer’s promotion for such use. The FDA Modernization Act of 1997 permitted sponsors to disseminate peer-reviewed studies from scientific journals about off-label uses that had been or would form part of a supplementary New Drug Application (sNDA). These provisions expired in September 2006 with the result that current law prohibits any promotion of a drug for unapproved uses. Recently, the FDA proposed new guidelines that enable sponsors to distribute publications about unapproved uses of approved drugs and devices. For drugs, for example, an sNDA is no longer required. The journal that published the article to be distributed must have both an editorial board that uses independent reviewers and a policy of full disclosure of conflict of interest; the article must be peer-reviewed; and the article should not be in a supplement funded by the sponsor. The information should address adequate and well-controlled clinical investigations and not be false, misleading, or pose a significant threat to health. Distribution is to include the product label, a relevant bibliography, and a representative publication, if it exists, that reaches a different conclusion about the unapproved use. Are these proposed changes consistent with the FDA’s mission of protecting the public health by ensuring the efficacy and safety of medications? Although peer-reviewed literature serves as the gold standard for evidence-based medicine, there are major limitations in relying on sponsordistributed literature to regulate off-label use, including the selective publication of studies, the systematic manipulation of the literature, the absence from the literature of critical data necessary for evaluating off-label use, and the potential for undermining the NDA review process.

Phase 0 Clinical Trials in Cancer Drug Development: From FDA Guidance to Clinical Practice

The Food and Drug Administration (FDA) recently introduced the Exploratory Investigational New Drug Guidance to expedite the clinical evaluation of new therapeutic and imaging agents. Early clinical studies performed under the auspices of this guidance, so-called "Phase 0" trials, have been initiated at the National Cancer Institute to integrate qualified pharmacodynamic biomarker assays into first-in-human cancer clinical trials of molecularly targeted agents. The goal of this integration is to perform molecular proof-of-concept investigations at the earliest stage of cancer drug development. Phase 0 trials do not offer any possibility of patient benefit; instead, intensive, real-time pharmacodynamic and pharmacokinetic analyses of patient tumor samples and/or surrogate tissues are performed to inform subsequent trials. Phase 0 studies do not replace formal Phase I drug safety testing and require a substantial investment of resources in assay development early on; however, they offer the promise of more rational selection of agents for further, large-scale development as well as the molecular identification of potential therapeutic failures early in the development process.

Drug's Availability Doesn't Mean FDA Has Approved It

Back to table of contents Previous article Next article Professional NewsFull AccessDrug's Availability Doesn't Mean FDA Has Approved ItJun YanJun YanSearch for more papers by this authorPublished Online:16 Nov 2007https://doi.org/10.1176/pn.42.22.0005There may be thousands of drug products being prescribed and dispensed to patients in the United States that have never been reviewed by the Food and Drug Administration (FDA) for safety and efficacy or approved for marketing. The agency is now taking steps to address the potentially large problem.In June 2006, the FDA released a guidance document, “Marketed Unapproved Drugs—Compliance Policy Guide,” to clarify the rules regarding drugs on the market that have not been reviewed or approved by the agency's normal process and the agency's plan to enforce them.Many of these unapproved drugs are advertised and listed in reference books such as the Physicians' Desk Reference, prescribed by physicians, and dispensed or sold to patients, according to the FDA guidance document. Physicians and pharmacists are usually not aware of the unapproved status of these drugs, which can be distributed based on a 10-digit number known as the National Drug Code (NDC). The NDC number is issued to all types of drug products, including unapproved investigational drugs, and does not guarantee a drug's approval status. These products' labeling information does not distinguish their approval status, nor is the labeling necessarily reviewed by the FDA for safety claims and indications.The FDA says on its Web site that most of these products remain on the market illegally for “a variety of historic reasons.” Most became available before the Federal Food, Drug, and Cosmetic Act was revised in the 1960s to require that a new drug be evaluated by the FDA for efficacy as well as safety. Before these regulations, new drugs only needed to be shown as safe, and drugs deemed the same or similar to approved drugs needed no independent review and approval process by the agency. The labels of these products may not conform to current regulatory standards and may carry unapproved claims and indications. Although the FDA had contracted with the National Academy of Sciences/National Research Council to evaluate the effectiveness of thousands of products approved only for safety between 1938 and 1962, not all products have gone through the approval process.Even the drug products deemed illegal have not all been forced off the market. Other provisions in the regulations have allowed older drugs without labeling updates to slip through the cracks.It is unknown how many currently marketed drugs are unapproved, and the agency does not maintain a complete list of these products. The guidance estimated that “several thousand drug products are marketed illegally without required FDA approval” today and admits that the agency is“ unable to take action immediately against all. . .illegally marketed products” because of a lack of resources.Since the release of the guidance last year, the FDA has been systematically issuing sanctions against certain unapproved products by demanding their withdrawal from the market or convincing some manufacturers to go through the official process by filing a New Drug Application for the agency's review in order to legalize their products and update the product labeling. A short list of drugs and manufacturers against which enforcement actions have already been taken is posted on the FDA's Web site.The guidance document claims that the enforcement priorities are given to drugs that have potential safety risks, lack evidence of effectiveness, are fraudulently promoted and sold, “present direct challenges to the new drug approval and [over-the-counter] drug monograph systems,” or are reformulated to evade FDA enforcement action. Priority is also given to unapproved new drugs that violate the regulations in other ways.In 2006, unapproved products containing quinine and carbinoxamine with unapproved labeling were targets. This September, the agency announced that it will take “enforcement action” against manufacturers of unapproved hydrocodone-containing cough syrups, citing reports of medication errors due to formulation changes in the unapproved products and confusion over their brand names. The agency is also concerned that “no hydrocodone cough suppressant has been established as safe and effective in children under 6 years of age, and some of these unapproved products carry labels with dosing instructions for children as young as 2 years old,” warned Steven Galson, M.D., M.P.H., director of the FDA's Center for Drug Evaluation and Research in a press release.The FDA Web page lists selected drugs and companies that have been cited for enforcement actions, but includes no psychiatric drugs. However, the FDA has not released a complete list of all unapproved drug products on the market. Psychiatrists may be treating patients who are taking, for example, unapproved hydrocodone, levothyroxine, and quinine products (for restless legs syndrome).Additional information about unapproved drugs and FDA actions is posted at<www.fda.gov/cder/drug/unapproved_drugs/default.htm>.“ Guidance for FDA Staff and Industry: Marketed Unapproved Drugs—Compliance Policy Guide” is posted at<www.fda.gov/cder/guidance/6911fnl.pdf>.▪ ISSUES NewArchived

The Mayo Clinic Manuscript Series Relative to the Discussion, Dissemination, and Operationalization of the Food and Drug Administration Guidance on Patient-Reported Outcomes

Abstract Patient-reported outcomes (PROs) have become increasingly prevalent in clinical research and practice. On February 2, 2006, the Food and Drug Administration (FDA) released a draft guidance document with respect to incorporating PROs into clinical research endeavors which include FDA involvement. Researchers at the Mayo Clinic worked with FDA personnel and experts from academia, industry, clinical research, and clinical practice to facilitate discussion, dissemination, and operationalization of the FDA guidance document. This article introduces a manuscript series that resulted from this collective effort. Basic terms are definedand a précis of each article in the manuscript series is given. The ultimate conclusion to be drawn from this series is that, while the goals of assessing and analyzing PRO elements of clinical practice and research are challenging, there now exists a scientific foundation that makes achieving these goals feasible and the results credible. This is vitally important because after all, at the heart of all healthcare endeavors is the patient.

Recommendations for Implementation of Community Consultation and Public Disclosure Under the Food and Drug Administration’s “Exception From Informed Consent Requirements for Emergency Research”

In addition to the usual requirement of appropriate study design and institutional review board (IRB) approval, research studies performed under the Food and Drug Administration (FDA) and Department of Health and Human Services regulations regarding “Informed Consent and Waiver of Informed Consent Requirements in Certain Emergency Research” (21 CFR §50.24)1 require community consultation and public disclosure. This special report discusses the general issues related to consent in emergency circumstances and provides a template to help IRBs implement community consultation and public disclosure appropriately. A portion of the material in this special report was presented as testimony by Dr Halperin on October 11, 2006, at the FDA’s public hearing on “Draft Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Exception From Informed Consent Requirements for Emergency Research.” More than 300 000 Americans die each year due to catastrophic medical and surgical emergencies.2,3 New interventions based on sound research could save lives. These research studies must be done within an ethical framework that traditionally includes obtaining prospective informed consent from the research subject. The ethical framework for the conduct of human research began with the development of the Nuremberg Code4,5 in 1949. This code states that (1) informed consent of volunteers must be obtained without coercion of any form, (2) human experiments should be based on prior animal experiments, (3) the anticipated scientific results should justify the experiment, (4) only qualified scientists should conduct medical research, (5) physical and mental suffering should be avoided, and (6) no expectation of death or disabling injury should be expected from the research study. The Declaration of Helsinki6 was issued in 1964 and defines rules for clinical research. It repeats the ethical concerns stated in the Nuremberg Code but also gives a provision for enrolling certain patients in clinical research without …

Current challenges for FDA‐regulated bioanalytical laboratories for human (BA/BE) studies, Part II: recent FDA Inspection trends for bioanalytical laboratories using LC/MS/MS methods and FDA Inspection readiness preparation

AbstractThis article is the second of a three‐part series that deals with the recent Food and Drug Administration (FDA) inspectional trends for bioanalytical laboratories performing analysis for human bioavailability (BA)/bioequivalence (BE) studies. While the FDA compliance expectations have been published in various FDA guidances, as well as the Compliance Program Guidance Manual for current Good Manufacturing Practice and Good Laboratory Practice (as discussed in Part 1 of this series), there are no specific regulations that mandate the operation and control of the bioanalytical laboratories conducting analyses for human BA/BE studies. It is apparent that the compliance standards and analytical testing requirements have been subject to a dynamically evolving process, slowly developed through several workshops jointly sponsored by the FDA and the pharmaceutical industry in the past decade. As the FDA expectations in the practices of bioanalytical laboratories become clearer, an increased trend is observed for the number of FDA 483 observations and untitled letters issued. This article provides a detailed analysis of the current FDA guidance and apparent expectations based on inspectional trends observed. In addition, the compliance and scientific basis of these dynamically evolving regulatory issues are also discussed, where applicable. Copyright © 2008 John Wiley &amp; Sons, Ltd.

Recruiting Healthy Volunteers for Research Participation via Internet Advertising

The Internet is frequently used as a tool to recruit research subjects, and the US Food and Drug Administration (FDA) provides general guidance regarding such advertising. The goal of this study was to explore the incidence and nature of ethically inappropriate recruiting advertisements on the Internet and to provide descriptive guidance to researchers for responsible Internet recruiting. In this study, 119 advertisements recruiting health volunteers and listed on the CenterWatch Clinical Trials Listing Service website were reviewed for content as well as text style and visual effects. The majority of advertisements satisfied FDA guidance. However, 21 (18%) were ethically troubling with regard to font size, font style, and/or verbiage. In many advertisements, it was unclear if "medication" meant "investigational drug," "over-the-counter medication" or US FDA approved "prescription medication." Nearly 30% of the 119 advertisements used the terms "free," "no charge" or "no cost" as lures. Ethically problematic recruiting advertisements can be coercive and misleading. Descriptive guidance provided in this paper can help clinical researchers create ethically appropriate recruiting advertisements.

Key elements of bioanalytical method validation for macromolecules

The Third American Association of Pharmaceutical Scientists/US Food and Drug Administration (FDA) Bioanalytical Workshop, which was held May 1 and 2, 2006, in Arlington, VA, addressed bioanalytical assays that are being used for the quantification of therapeutic candidates in support of pharmacokinetic evaluations. One of the main goals of this workshop was to discuss best practices used in bioanalysis regardless of the size of the therapeutic candidates. Since the last bioanalytical workshop, technological advancements in the field and in the statistical understanding of the validation issues have generated a variety of interpretations to clarify and understand the practicality of using the current FDA guidance for assaying macromolecular therapeutics. This article addresses some of the key elements that are essential to the validation of macromolecular therapeutics using ligand binding assays. Because of the nature of ligand binding assays, attempts have been made within the scientific community to use statistical approaches to interpret the acceptance criteria that are aligned with the prestudy validation and in-study validation (sample analysis) processes. We discuss, among other topics, using the total error criterion or confidence interval approaches for acceptance of assays and using anchor calibrators to fit the nonlinear regression models.

Key elements of bioanalytical method validation for small molecules

Method validation is a process that demonstrates that a method will successfully meet or exceed the minimum standards recommended in the Food and Drug Administration (FDA) guidance for accuracy, precision, selectivity, sensitivity, reproducibility, and stability. This article discusses the validation of bioanalytical methods for small molecules with emphasis on chromatographic techniques. We present current thinking on validation requirements as described in the current FDA Guidance and subsequent 2006 Bioanalytical Methods Validation Workshop white paper.

Classification of torasemide based on the Biopharmaceutics Classification System and evaluation of the FDA biowaiver provision for generic products of Class I drugs

The biopharmaceutical properties of an in-house developed new crystal modification of torasemide (Torasemide N) were investigated in comparison with the most well known crystal modification form of torasemide (Torasemide I) in order to classify the drug according to the Biopharmaceutics Classification System (BCS), and to evaluate the data in line with current US Food and Drug Administration (FDA) guidance (with biowaiver provision for Class I drugs) to determine if the biowaiver provision could be improved. The solubility profiles of Torasemide I and Torasemide N were determined, and tablets prepared from both forms of the drug were studied for in-vitro release characteristics in media recommended by the current FDA guidance for biowaiver of generic products, and in other media considered more appropriate for the purpose than the ones recommended by the FDA. Two separate bioequivalence studies in healthy humans (following oral administration) were performed with two test products (both prepared from Torasemide I) against a single reference product (prepared from Torasemide N). The absorption profiles of the drug from the tablets were determined by deconvolution for comparison with the in-vitro release profiles to determine the appropriateness of some dissolution media for predicting in-vivo performance and to determine the comparative rate and extent of absorption. The drug was absorbed from the tested products quickly and almost completely (about 95% within 3.5 h of administration). However, one test product failed to meet the bioequivalence criteria and had a significant initial lower absorption rate profile compared with the reference product (P< or =0.05), whereas the other product was bioequivalent and had a similar absorption profile to the reference product. A dissolution medium at pH 5.0, in which torasemide has minimum solubility, was found to be more discriminatory than the media recommended by the FDA. Torasemide has been classified as a Class I drug according to the BCS up to a maximum dose of 40 mg and the data suggest that the current FDA guidance could be improved by giving more emphasis to selection of appropriate dissolution media than is given in its current form for approving biowaiver to generic products of Class I drugs.

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