Food And Drug Administration 's Approach Research Articles

Prospect of Direct Benefit in Pediatric Trials: Practical Challenges and Potential Solutions.

Clinical research in pediatric patients is necessary to develop safe and effective medicines for children. US Food and Drug Administration (FDA) human subject protection regulations (21 Code of Federal Regulations 50, subpart D) require that, with limited exceptions, research in children that exceeds a defined level of risk must offer a prospect of direct benefit to the individual child that is sufficient to justify those risks. Growing attention to the merits of initiating pediatric clinical trials earlier in the drug and biological product development process has led the FDA to look more closely at the meaning of the regulatory term prospect of direct benefit. In collaboration with the FDA, the Duke-Margolis Center for Health Policy convened a workshop with leading experts in the fields of biomedical ethics, pediatric clinical research, and pediatric product development, as well as patient representatives, to discuss the FDA's approach to characterizing prospect of direct benefit in the context of scientific advances in product development. Workshop topics included the extrapolation of adult efficacy data to children, use of nonclinical models of disease, use of modeling and simulation to support pediatric dosing, and reliance on biomarkers and surrogate end points in clinical research. Discussion from the workshop is provided herein to communicate the challenges that investigators, industry sponsors, regulators, and institutional review boards face when evaluating pediatric research and to outline several approaches to maximize prospect of direct benefit, minimize unnecessary risks and burden, and facilitate timely access to safe and effective medicines for children.

Symposium Introduction: A Decade of the Tobacco Control Act: Progress, Setbacks, and the Future of Tobacco Control

The landmark symposium, A Decade of the Tobacco Control Act: Progress, Setbacks, and the Future of Tobacco Control, organized by the Public Health Law Center and held in conjunction with the 2019 National Conference on Tobacco or Health, assessed the first 10 years of federal tobacco regulation. In this introduction to the symposium, the Public Health Law Center’s executive director provides the context for insights by prominent experts from government, health organizations, and academia, acknowledging the mixed record of U.S. Food and Drug Administration (FDA) regulation to date and suggesting that the agency’s ultimate success or failure will be determined by the answers to three fundamental, but still unresolved, questions: What is the true goal of federal regulation? How boldly or cautiously will the FDA approach that goal? And who will the agency serve? The answers to those questions, he argues, will determine the prospects for progress in controlling the nation’s leading cause of preventable death.

An Overview Of Vaccine Development, Approval, And Regulation, With Implications For COVID-19.

The Food and Drug Administration (FDA) approves vaccines when their benefits outweigh the risks for their intended use. In this article we review the standard FDA approach to vaccine evaluation, which underpins its current approaches to assessment of vaccines to prevent coronavirus disease 2019 (COVID-19). The FDA has established pathways to accelerate vaccine availability before approval, such as Emergency Use Authorization, and to channel resources to high-priority products and allow more flexibility in the evidence required for approval, including accelerated approval based on surrogate markers of effectiveness. Among the thirty-five new vaccines approved in the US from 2006 through October2020, about two-thirds of their pivotal trials used the surrogate outcome of immune system response, and only one-third evaluated actual disease incidence. Postapproval safety surveillance of new vaccines, and particularly vaccines receiving expedited approval, is crucial. This has generally been accomplished through such mechanisms as the Centers for Disease Control and Prevention (CDC) and FDA Vaccine Adverse Event Reporting System, the CDC Vaccine Safety Datalink, and the CDC Clinical Immunization Safety Assessment Project. Adverse events detected in this way may lead to changes in a vaccine's recommended use or withdrawal from the market. Regulatory oversight of new vaccines must balance speed with rigor to effectively address the pandemic.

Bioequivalence for highly variable drugs: regulatory agreements, disagreements, and harmonization.

Regulatory authorities introduced procedures in the last decade for evaluating the bioequivalence (BE) for highly variable drugs. These approaches are similar in principle but differ in details. For example, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recommend differing regulatory constants. The constant suggested by FDA results in discontinuity of the BE limits around the switching variation at 30% observed within-subject variation of the reference product. The regulatory constant of EMA does not have these problems. The Type I error reaches 6-7% around the switching variation with the EMA constant but 16-17% with the FDA constant. Various procedures were recently suggested, especially for the EMA approach, to eliminate the inflation of the Type I error. Notably, the so-called Exact algorithms try to amalgamate the positive features of both EMA and FDA procedures without their negative sides. The computational procedure for the EMA approach is simple and has a straightforward interpretation. The procedure for the FDA approach is based on an approximation, has a bias at small degrees of freedom, and requires a suitable computer program. All regulatory agencies impose a second requirement constraining the point estimate of the ratio of geometric means. In addition, EMA and Health Canada impose an upper limit for applying the recommended procedures. These expectations have psychological motivation and political rationale but no scientific foundations. Their inclusion results in incorrect and misleading interpretation of the principal criterion which involves confidence intervals. Different regulatory authorities expect to apply their approaches either to both AUC and Cmax or only to AUC or only to Cmax. Rational resolution of the disharmonization is needed.

An Exact Procedure for the Evaluation of Reference-Scaled Average Bioequivalence.

Reference-scaled average bioequivalence (RSABE) has been recommended by Food and Drug Administration (FDA), and in its closely related form by European Medicines Agency (EMA), for the determination of bioequivalence (BE) of highly variable (HV) and narrow therapeutic index (NTI) drug products. FDA suggested that RSABE be evaluated by an approximating procedure. Development of an alternative, numerically exact approach was sought. A new algorithm, called Exact, was derived for the assessment of RSABE. It is based upon the observation that the statistical model of RSABE follows a noncentral t distribution. The parameters of the distribution were derived for crossover and parallel-group study designs. Simulated BE studies of HV and NTI drugs compared the power and consumer risk of the proposed Exact method with those recommended by FDA and EMA. The Exact method had generally slightly higher power than the FDA approach. The consumer risks of the Exact and FDA procedures were generally below the nominal error risk with both methods except for the partial replicate design under certain heteroscedastic conditions. The estimator of RSABE was biased; simulations demonstrated the appropriateness of Hedges' correction. The FDA approach had another, small but meaningful bias. The confidence intervals of RSABE, based on the derived exact, analytical formulas, are uniformly most powerful. Their computation requires in standard cases only a single-line program script. The algorithm assumes that the estimates of the within-subject variances of both formulations are available. With each algorithm, the consumer risk is higher than 5% when the partial replicate design is applied.

Determination of β-N-methylamino-L-alanine, N-(2-aminoethyl)glycine, and 2,4-diaminobutyric acid in Food Products Containing Cyanobacteria by Ultra-Performance Liquid Chromatography and Tandem Mass Spectrometry: Single-Laboratory Validation.

A single-laboratory validation study was completed for the determination of β-N-methylamino-L-alanine (BMAA), N-(2-aminoethyl)glycine (AEG), and 2,4-diaminobutyric acid (DAB) in bulk natural health product supplements purchased from a health food store in Canada. BMAA and its isomers were extracted with acid hydrolysis to free analytes from protein association. Acid was removed with the residue evaporated to dryness and reconstituted with derivatization using 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AccQ-Fluor). Chromatographic separation and detection were achieved using RP ultra-performance LC coupled to a tandem mass spectrometer operated in multiple reaction monitoring mode. Data from biological samples were evaluated for precision and accuracy across different days to ensure repeatability. Accuracy was assessed by spike recovery of biological samples using varying amino acid concentrations, with an average recovery across all samples of 108.6%. The analytical range was found to be 764-0.746 ng/mL prior to derivatization, thereby providing a linear range compatible with potentially widely varying analyte concentrations in commercial health food products. Both the U. S. Food and Drug Administration (FDA) and U. S. Pharmacopeia definitions were evaluated for determining method limits, with the FDA approach found to be most suitable having an LOD of 0.187 ng/mL and LLOQ of 0.746 ng/mL. BMAA in the collected specimens was detected at concentrations lower than 1 μg/g, while AEG and DAB were found at concentrations as high as 100 μg/g. Finding these analytes, even at low concentrations, has potential public health significance and suggests a need to screen such products prior to distribution. The method described provides a rapid, accurate, and precise method to facilitate that screening process.

To monitor dabigatran or not: a matter of patient safety.

In October 2010, the US Food and Drug Administration (FDA)2 approved dabigatran etexilate (Pradaxa), a new oral, direct thrombin inhibitor, for prevention of stroke and thrombosis in patients with nonvalvular atrial fibrillation (AF). This marked a new era in the development of fixed-dose novel oral anticoagulants (NOACs) with the hope of achieving improved safety and clinical outcomes compared with warfarin. The concept of a fixed-dose anticoagulant that requires no monitoring quickly made the transition from concept to practice, helped partially by the FDA's new approach to innovative therapies. This new approach gave the manufacturer, Boehringer Ingelheim, access to priority reviews and a shorter approval process for its blockbuster drug, dabigatran. Rather than the conventional requirement of at least 2 pivotal trials, only a single large clinical trial was necessary for approval. Fixed-dose dabigatran demonstrated noninferior performance compared with dose-optimized warfarin therapy in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial for prevention of stroke and thrombosis in patients with nonvalvular AF, thus providing the bulk of support for FDA approval. After approval by the FDA in 2010 and the European Medicines Agency (EMA) a year later, dabigatran's popularity grew quickly, and by the end of 2013 sales approached $2 billion. However, amid litigation in US courts that centered on claims that dabigatran caused severe and fatal bleeding in patients, an investigation by the British Medical Journal revealed that as far back as 2010 Boehringer Ingelheim had knowledge that adjusting the dose of dabigatran might provide patients with superior efficacy and safety compared with a fixed dose (1, 2). This raised serious concerns about what the manufacturer chose not to disclose as it sought regulatory approval. The clinical impetus to explore novel anticoagulants originated from the difficulty in managing anticoagulation in patients receiving the standard-of-care treatment, warfarin. Anticoagulation …

An evaluation of the FDA's analysis of the costs and benefits of the graphic warning label regulation

The Family Smoking Prevention and Tobacco Control Act of 2009 gave the Food and Drug Administration (FDA) regulatory authority over cigarettes and smokeless tobacco products and authorised it to assert...

Regulatory and Scientific Issues Regarding Use of Foreign Data in Support of New Drug Applications in the United States: An FDA Perspective

Globalization of clinical research has led to an increase in clinical trials conducted outside of the United States that are submitted to the US Food and Drug Administration (FDA) in new drug applications. This article discusses the FDA's experience with these submissions in specific therapeutic areas, including the extent of this practice, differences between the effectiveness and safety outcomes of studies conducted inside and outside the United States, and the FDA's approach to acceptance of these trials.

Caffeine: Public Concern and the Precautionary Principle

Caffeine: Public Concern and the Precautionary Principle

Perspectives on How FDA Assesses Exposure to Food Additives When Evaluating Their Safety: Workshop Proceedings

AbstractFood additives and substances considered “generally recognized as safe” must not be allowed in food unless there is a reasonable certainty in the minds of competent scientists that the substance is not harmful under the intended conditions of use. Scientists determine safety by ensuring that the expected exposure is less than the acceptable daily intake. The U.S. Food and Drug Administration (FDA) provides guidance documents to assist safety assessors in this analysis. A November 2011 workshop sponsored by The Pew Charitable Trusts, the Institute of Food Technologists, and the journal Nature reviewed the agency's exposure assessment approaches. More than 70 experts from government (including FDA), industry, academia, and public interest organizations examined the principles underlying dietary exposure assessments for substances added to human food, and responded to questions about current methods. FDA's approach was seen as serving the agency reasonably well, but participants identified opportunities for improvement. Although reaching a consensus was not a goal, general agreements emerged that FDA should develop a science‐based framework to prioritize and reassess prior safety decisions, and conduct more extensive postmarket monitoring. Participants discussed the possibility of harmonizing different approaches to assess dietary exposure. They generally agreed that collaboration, communication, and exchanging scientific information between agencies and stakeholders would help assessors use the most current information to make better decisions. Participants identified data gaps and opportunities to fill the gaps using new tools and technologies. Participants generally agreed on the need to consider all dietary sources in a cumulative dietary exposure assessment.

Vilazodone

Vilazodone was recently approved by the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD). The purpose of this review is to summarize the FDA's approach to its review of the clinical pharmacology and the clinical efficacy and safety data for this new drug application, important issues in its decision-making, and its conclusions. The data sources for this review were the original raw data sets for all clinical trials included in the development program for vilazodone, as well as the sponsor's original analyses of these data. Data were available from 24 human trials involving vilazodone, and included a total of 2,898 human subjects exposed to 1 or more doses of this drug. The FDA had access to original raw data sets for these trials. Vilazodone is effective in treating MDD at a dose of 40 mg/d, but it needs to be incrementally adjusted to this dose to minimize gastrointestinal symptoms. It needs to be taken with food to ensure adequate plasma concentrations. Vilazodone's profile of adverse events is similar to that seen with selective serotonin reuptake inhibitors. No dose adjustment is needed based on age, gender, or renal or hepatic impairment. It is recommended that the vilazodone dose be reduced to 20 mg when it is taken with strong cytochrome P450 (CYP) 3A4 inhibitors, eg, ketoconazole. Vilazodone is not expected to have important effects on the clearance of other drugs that are cytochrome P450 substrates. Vilazodone is a new treatment for MDD, but it is unknown whether it has any advantages compared to other drugs in the antidepressant class.

FDA's proposed rule for pregnancy and lactation labeling: improving maternal child health through well-informed medicine use.

For the US Food and Drug Administration (FDA), the May 29,2008 publication of the Proposed Rule for Pregnancy and Lactation Labeling for Human Prescription Drug and Biological Products heralded both an end and a beginning. It marked an end to the labeling initiative process that produced the Proposed Rule and the beginning of FDA's second-generation approach to labeling drugs and biologics for use during pregnancy, breastfeeding, and the childbearing years. These proposed changes reflect the extensive input and feedback FDA collected from clinicians and experts, and are designed to facilitate informed counseling about and prescribing of medicines for women who are pregnant, breastfeeding, or of childbearing potential. The prescription drug label is FDA's communication tool-it is the place to clearly convey what is known about the safe and effective use of a drug in various populations. With development and implementation of the Physician Labeling Rule (PLR), FDA transformed the prescription drug label into a better communication tool in which information is better organized, clearly presented, and more easily located. The Proposed Rule for Pregnancy and Lactation Labeling is the final piece of PLR, creating a detailed and defined framework in which to present what is and is not known about the use of drugs during pregnancy and breastfeeding.

Steering a course for risk assessment: The impact of new draft guidance, 21 CFR part 11, scope and application, on the electronic records; electronic signatures rule

AbstractAs a result of some re‐organization in the US Food and Drug Administration (FDA) and the introduction of the CGMP risk‐based approach, 21 CFR Part 11 is being revisited. The FDA has decided to re‐evaluate Part 11 and during the re‐evaluation, the FDA issued guidance on how Part 11 will be interpreted. The proposed guidance defines the FDA's approach to the scope and application of Part 11. The draft guidance has substantial regulatory impact by withdrawing previous Part 11 draft guidance as well as the Compliance Policy Guide 71523.17.The scope of Part 11 is defined to be records required by predicate rules kept electronically in lieu of paper records or relied upon for regulated activities, as well as records submitted to the agency, and electronic signatures. Emphasis is given to following predicate rule requirements.In applying Part 11, the FDA will exercise enforcement discretion in the areas of audit trail requirements, validation, copying electronic records, electronic record maintenance, and legacy systems. Emphasis is given to creating and following documented Risk Assessment practice.This article examines the change in FDA focus and highlights key points in the draft guidance. Further, this article provides practical advice for industry, provides an overview on comments (industry feedback) submitted to the Agency on the guidance, and provides an interpretation of the likely direction for future Part 11 regulation. Copyright © 2003 John Wiley & Sons, Ltd.

Testing the FDA's Mandate for Over-the-Counter Medication Labels

ABSTRACTThe Food and Drug Administration (FDA) has recently attempted to improve the safety of over-the-counter (OTC) drugs by creating a regulation aimed at redesigning their labels. One portion of this regulation attempts to improve the legibility of OTC labels by individually specifying certain elements of their design. The FDA's approach looks at the elements of label design as distinct entities that can be isolated and manipulated to improve legibility. Reality does not match the simplicity of this approach. Legibility is the overall goal in a complex system of interrelated elements that come together to create a message. This research challenges the regulation by using an instrument that measures what is truly important: the legibility of the label.

Biotechnology at the Dinner Table: FDA's Oversight of Transgenic Food

The U.S. Food and Drug Administration (FDA), which has statutory authority for protecting the safety and quality of the food supply, provides the oversight for genetically modified foods cultivated and marketed within the American agricultural system. This article examines the FDA's policies on genetically modified foods including its voluntary consultation program and its proposed rule on premarket notification and data submission. The FDA's consultations of foods modified for delayed ripening and herbicide tolerance are reviewed. The article also discusses the FDA's science-based approach for evaluating whether there are any potential adverse health effects of genetically modified food products. The agency has chosen an approach to risk assessment that takes account of both product characteristics and the process through which the food is developed.

Comparison of Derived Intervention Levels for Accidental Contamination of Food Using Effective Dose Equivalent (HE) and Effective Dose (E)

Recommendations on accidental radioactive contamination of human food and animal feeds were issued in 1982 by the United States Food and Drug Administration (FDA) as guidance to State and local government officials. In a proposed update of the recommendations, FDA employed the quantity effective dose equivalent (H E ), which is the quantity currently used by all Federal agencies in the United States. In 1990, a modified version of H E called effective dose (E) was introduced by ICRP. This paper compares the Derived Intervention Levels for radionuclides relevant to accidental contamination of food, employing H E and E for the same intervention level of dose. For seven bone-seeking radionuclides, the Derived Intervention Levels for E, using the FDA approach, increase by factors of 3.4 to 8.8 compared to those using H E . For three radioiodines, the Derived Intervention Levels for E increase by a factor of two compared to those using H E . For the remaining radionuclides, the ratios of Derived Intervention Levels for E to H E are in the range of 0.8 to 1.2.

FDA's Approach to International Harmonization of Biomaterials and Tissue-Engineered Products

The possibilities for global regulation of tissue-engineered products are discussed. While issues of national sovereignty are likely to present difficulties, the international medical device community shares fundamental goals, and the potential benefits to global harmonization are substantial. The Food and Drug Administration (FDA) is collaborating currently with international organizations on an approach to attain these goals, with excellent results. The devices approach to harmonization presented at the meetings of the Global Harmonization Task Force in June 1995 is described. FDA believes a stepwise approach to harmonization is an effective and efficient approach to making progress. To do this, all parties must agree on steps to achieve harmonization in each area. It is highly desirable that each country reach the same definitions of tissue and tissue-engineered products and jurisdictional assignments for regulatory review, avoiding overlaps, so that the industry can deal more economically with regulat...

Foods of the Future

ALTHOUGH most of the genetically altered of the future are similar to the foods we are familiar with, the techniques of the new biotechnology are subtly changing and improving the foods we eat. The Food and Drug Administration (FDA) already has paved the way for the arrival of the new food products and processes by announcing on May 29, 1992, its policy on the oversight of new varieties of food plants. 1 But because of the scientific issues involved (eg, allergenicity) as well as consumers' reservations about such products and their general lack of understanding of the FDA's policy, it is important that physicians—a trusted source of health-related advice—be informed on the nuances of the subject. This article attempts to place in a scientific perspective new crop varieties obtained by conventional and new techniques and describes the FDA's approach to their oversight. The History of Genetic Engineering Applied to

Regulation of “Biomaterials” and Medical Devices

On May 28, 1976, President Gerald R. Ford signed into law the Medical Device Amendments to the Federal Food, Drug and Cosmetic Act. The purpose of the Amendments is to ensure that medical devices are safe and effective, and properly labelled for their intended use. In order to accomplish this mandate, the Amendments provide the Food and Drug Administration (FDA) with authority to regulate devices during most phases of their development, testing, and use. The FDA's approach to this regulation focuses heavily on both the pre- and post-market phases of a device's lifetime. During the pre-market phase, the FDA concentrates on providing a reasonable assurance that new devices are adequately evaluated for safety and effectiveness. Implicit in this assessment is the concept of balancing risk to benefit. If the benefits significantly outweigh the risks for the intended use, the device will most likely be approved for marketing in the United States. Since risk/benefit assessments for new technology involve considerable clinical judgment, the FDA utilizes expert panels composed of clinicians, engineers, toxicologists, and other experts familiar with the devices. These panels are often directed to review the data provided by the manufacturer to support claims for device safety and effectiveness. If the advisory panel believes the data support the manufacturer's claims, a recommendation for approval for marketing is made to the FDA. The Agency must ultimately decide whether the device is to receive approval for marketing.