Drug Administration Draft Research Articles

Abuse liability assessment of hydrocodone under current draft regulatory guidelines

IntroductionThe abuse liability of hydrocodone was assessed in male Sprague–Dawley rats under the European Medicines Agency, the International Commission on Harmonisation, and the U.S. Food & Drug Administration draft guidelines for the non-clinical investigation of the dependence potential of medicinal products. MethodsSelf-administration, drug discrimination, and repeat-dose two week dependence liability studies were conducted to compare hydrocodone to the prototypical opiates, morphine and oxycodone. ResultsHydrocodone was self-administered, produced an opiate-like subjective discriminative generalization profile and produced a significant discontinuation syndrome following abrupt treatment cessation that was quantitatively and qualitatively similar to morphine and/or oxycodone. ConclusionHydrocodone has abuse liability more similar to Schedule II opiates than other Schedule III compounds currently controlled under the U.S. Controlled Substance Act.

Drugs and Diseases Interacting with Cigarette Smoking in US Prescription Drug Labelling.

The US Food and Drug Administration (FDA) draft guidance for industry on drug interaction studies recommends, but does not mandate, that both cigarette smokers and non-smokers can be used to study drug metabolism in clinical trials, and that important results related to smoking should be included in drug labelling to guide medication usage. This study aimed to provide a comprehensive review of drugs or diseases interacting with smoking, as presented in all US drug labelling. The 62,857 drug labels deposited in the FDA Online Label Repository were searched using the keywords 'smoke', 'smoker(s)', 'smoking', 'tobacco' and 'cigarette(s)' on 19 June 2014. The resultant records were refined to include only human prescription drug labelling, for manual examination. For 188 single-active-ingredient drugs and 36 multiple-active-ingredient drugs, the labelling was found to contain smoking-related information. The pharmacokinetics of 29 and 21 single-active-ingredient drugs were affected and unaffected, respectively, by smoking. For the remaining drugs, the provided information related to smoking affecting efficacy, safety or diseases but not pharmacokinetics. Depending on the nature of specific drugs, the perturbation in pharmacokinetic parameters in smokers ranged from 13 to 500%, in comparison with non-smokers. Dosage modifications in smokers are necessary for four drugs and may be necessary for six drugs, but are unnecessary for seven drugs although the pharmacokinetic parameters of four of them are affected by smoking. Cigarette smoking is a risk factor for 16 types of diseases or adverse drug reactions. For one single-active-ingredient contraceptive drug and 10 multiple-active-ingredient contraceptive drugs, a black box warning (the FDA's strongest safety warning) is included in the labelling for increased risks of heart attacks and strokes in female smokers, and "women are strongly advised not to smoke" when using these drugs. This study presents the first comprehensive overview of cigarette smoking interacting with drugs and/or diseases, as presented in US drug labelling.

Clinical considerations for the development of biosimilars in oncology

Despite availability of biologic therapies, limited patient access to many of the most-effective cancer treatments affects overall health outcomes. To address this issue, many governments have enacted legislation for the approval of biosimilars. The term “biosimilar” refers to a biologic product that is developed to be highly similar, as opposed to identical, to a licensed biologic product (the reference or innovator product), such that, per US Food and Drug administration draft guidelines, “no clinically meaningful differences [exist] between the biological product and the reference product in terms of safety, purity, and potency.” This article presents some considerations about the development of biosimilars in cancer treatment through an overview of biosimilars from a clinical perspective. Topics covered include the development requirements and unique regulatory requirements for biosimilars, labeling considerations, potential limitations to the uptake of biosimilars, and review of some biosimilars in development for oncology indications.

Compliance Within Medical Information and the Emergence of a Medical Information-Dedicated Compliance Person: A Benchmarking Survey.

In light of the increasing scrutiny by governing authorities, compliance requirements for medical information (MI) departments have increased over the past few years. In response to the Food and Drug Administration (FDA) draft guidance for industry, entitled Responding to Unsolicited Requests for Off-label Information About Prescription Drugs and Medical Devices, MI groups may be changing their policies and procedures to further ensure compliance. The primary objective of this study was to benchmark industry-specific practices related to maintaining compliance in MI, particularly whether there is an emergence of a dedicated compliance person working within the MI department, whom we refer to as the MI-dedicated compliance person hereafter. A secondary objective was to identify changes to MI interactions with internal and external stakeholders that occurred in the last 2 years in response to an evolving regulatory climate. A web-based survey was disseminated to MI professionals from 49 companies between December 2012 and February 2013. Practices that were assessed include MI team training, monitoring, audits, and creation of letter responses. The results may be useful for MI groups interested in changing or comparing their compliance practices to those currently utilized by their peers.

A Review of FDA Warning Letters and Notices of Violation Issued for Patient-Reported Outcomes Promotional Claims between 2006 and 2012

ObjectiveTo ascertain the frequency and types of patient-reported outcome (PRO) violations made in US pharmaceutical promotional materials between 2006 and 2012 and determine whether there were increases in violation warnings after issuance of the Food and Drug Administration (FDA) draft and final PRO Guidance. MethodsAll warning letters (WLs) or notices of violation (NOVs) issued by the FDA’s Office of Prescription Drug Promotion were reviewed for PRO violations (n = 213). Each letter containing a PRO violation was reviewed to determine the type of violation: 1) PRO measure not fit for purpose, 2) study design/interpretation of results, 3) statistical analysis, and 4) no treatment benefit. ResultsForty-one (19%) letters contained information about PRO infringements. Noticeable spikes in letters were shown in 2007 (37%) and 2010 (31%) after the issuance of the draft and final PRO Guidance, respectively. The most common violation was PRO measure not fit for purpose (54%), specifically: use of individual items (45%), insufficient evidence of content validity (36%), and broadening of the claim beyond what the PRO measures (27%). Issues with study design/interpretation of results were also high (49%), particularly broadening of claim beyond what was measured in the trial (55%) and no PRO measure used (50%). ConclusionsA fifth of the letters issued to companies contained PRO violations, with most related to poor selection of the PRO measure used or trying to broaden the claim. More guidance from the Office of Prescription Drug Promotion about what is considered “substantial evidence” in this area could help reduce the number of letters issued.

Comparison of in vitro release rates of acyclovir from cream formulations using vertical diffusion cells.

Acyclovir, indicated in the treatment of herpes labialis ("cold sores"), is formulated as semisolid topical dosage forms and marketed in numerous countries. Since the formulations of the various acyclovir products may differ from country to country, this study was undertaken to compare the in vitro release of acyclovir from various generic cream products available on the South African and Indian markets using the respective brand/innovator product as the reference product. The in vitro studies were carried out using vertical diffusion cells with a diffusional surface area of 1.767cm(2) and various commercially available membranes. Normal saline was used as receptor fluid and the temperature maintained at 32 ± 0.5°C. The in vitro release comparisons were based on the recommendations described in the US Food and Drug Administration Draft Guidance for acyclovir ointment and the SUPAC-SS Guidance for non-sterile semisolid dosage forms. The release rates (slope) of the test (T) and the relevant reference product (R) were monitored and compared. The comparative release of acyclovir from the various generic formulations compared with the reference product was found to be within the limits of 75-133.33% with a 90% confidence interval. These experiments indicate that the generic acyclovir cream formulations exhibited release rates that were comparable to the innovator product and could be considered to be bioequivalent.

Rethinking the Food and Drug Administration's 2013 guidance on developing drugs for early-stage Alzheimer's disease

The February 2013 Food and Drug Administration (FDA) draft guidance for developing drugs for early-stage Alzheimer's disease (AD) creates certain challenges as they guide toward the use of one cognitive outcome to gain accelerated marketing approval for preclinical AD drugs, and a composite clinical scale – the Clinical Dementia Rating Scale in particular – for the primary outcome for prodromal AD clinical trials.In light of the developing knowledge regarding early stage diagnoses and clinical trials outcomes, we recommend that FDA describe its requirements for validating preclinical AD diagnoses for drug development purposes, maintain the principle for requiring coprimary outcomes, and encourage the advancement of outcomes for early stage AD trials. The principles for drug development for early stage AD should not differ from those for clinical AD, especially as the diagnoses of prodromal and early AD impinge on each other. The FDA should not recommend that a composite scale be used as a sole primary efficacy outcome to support a marketing claim unless it requires that the cognitive and functional components of such a scale are demonstrated to be individually meaningful. The current draft guidelines may inadvertently constrain efforts to better assess the clinical effects of new drugs and inhibit innovation in an area where evidence-based clinical research practices are still evolving.

Evaluation of 23 Lots of Commercially Available Cryopreserved Hepatocytes for Induction Assays of Human Cytochromes P450

Due to the importance of in vitro cytochrome P450 (P450) induction assay to assess the possible drug-drug interaction events, the recent US Food and Drug Administration draft guidance and European Medicines Agency guideline recommend to assess P450 induction using fresh or cryopreserved hepatocytes at mRNA level and/or enzyme activity level. Although cryopreserved hepatocytes are commercially available for P450 induction assays, feasibility and practicability of these hepatocytes have not been fully investigated. In this study, a total of 23 lots of human cryopreserved hepatocytes were treated with three typical inducers (omeprazole, phenobarbital, and rifampicin), and induction of CYP1A2, CYP2B6, and CYP3A4 enzyme activity was measured. In 8 of these 23 hepatocyte lots, induction of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 mRNA was also analyzed. The results revealed that CYP1A2, CYP2B6, and CYP3A4 were induced (>2.0-fold) by omeprazole, phenobarbital, and rifampicin, respectively, in all the hepatocyte lots tested at enzyme activity level (23 lots) and mRNA level (8 lots). In contrast, of the 8 hepatocyte lots treated with rifampicin, CYP2C8 and CYP2C9 mRNA were not induced in 5 and 2 hepatocyte lots, respectively, and CYP2C19 mRNA was not induced in any of the 8 hepatocyte lots tested. These results suggest that induction of CYP1A2, CYP2B6, and CYP3A4 can be readily assessed, but evaluation for CYP2C mRNA induction might not be feasible, using commercially available human cryopreserved hepatocytes.

Adaptive Clinical Trial Design

In recent years, the use of adaptive design methods in clinical trials based on accumulated data at interim has received much attention because of its flexibility and efficiency in pharmaceutical/clinical development. In practice, adaptive design may provide the investigators a second chance to modify or redesign the trial while the study is still ongoing. However, it is a concern that a shift in target patient population may occur after significant adaptations are made. In addition, the overall type I error rate may not be preserved. Moreover, the results may not be reliable and hence are difficult to interpret. As indicated by the US Food and Drug Administration draft guidance on adaptive design clinical trials, the adaptive design has to be a prospectively planned opportunity and should be based on information collected within the study, with or without formal statistical hypothesis testing. This article reviews the relative advantages, limitations, and feasibility of commonly considered adaptive designs in clinical trials. Statistical concerns when implementing adaptive designs are also discussed.

Telavancin for Hospital-Acquired Pneumonia: Clinical Response and 28-Day Survival

U.S. Food and Drug Administration draft guidance for future antibiotic clinical trials of bacterial nosocomial pneumonia recommends the use of diagnostic criteria according to American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines and the use of a primary endpoint of 28-day all-cause mortality. The effect of applying these guidelines on outcomes of phase III nosocomial pneumonia studies of telavancin was evaluated in a post hoc analysis. ATS/IDSA criteria were applied in a blind fashion to the original all-treated (AT) group. Clinical cure rates at final follow-up were determined in the refined AT and clinically evaluable (CE) groups (ATS/IDSA-AT and ATS/IDSA-CE, respectively). The exploratory endpoint of 28-day survival was evaluated for the ATS/IDSA-AT group. Noninferiority of telavancin versus vancomycin was demonstrated, with similar cure rates in the ATS/IDSA-AT (59% versus 59%) and ATS/IDSA-CE (83% versus 80%) groups. Cure rates favored telavancin in ATS/IDSA-CE patients where Staphylococcus aureus was the sole pathogen (86% versus 75%). Overall, 28-day survival rates were similar in the telavancin (76%) and vancomycin (77%) groups but lower in telavancin-treated patients with preexisting moderate-to-severe renal impairment (creatinine clearance [CLCR] of <50 ml/min). Telavancin should be administered to patients with moderate-to-severe renal impairment only if treatment benefit outweighs the risk or if no suitable alternatives are available.

Inference from blinded data in randomized clinical trials

With blinded data, several authors have concluded that there is a negligible chance of inferring a non-null treatment effect. The recent Food and Drug Administration (FDA) draft guidance document on adaptive trials, by encouraging blinded sample size reestimation, implies the same. We derive methods to investigate whether the probability of inferring a treatment effect is much larger than previously thought, and whether that is of concern. A statistic is developed that contributes to improving signal detection. Additionally, trials that are overpowered, for reasons external to powering the primary objective, further strengthen the chance of finding a signal. An example of data from a clinical trial shows how revealing a blinded analysis can be. The ability to infer a non-null effect while a blinded trial is ongoing is a serious matter. The methods apply to superiority trials and are of limited use for non-inferiority or equivalence trials. It is important, therefore, that guidance documents include clear language to limit or prevent inference from blinded data to maintain trial integrity. Simple steps are proposed to make inference difficult.

Assessing the Impact of Heart Failure Therapeutics on Quality of Life and Functional Capacity

Chronic heart failure (CHF) is an increasingly common disorder with major impact on morbidity and mortality. Goals of therapy include improving survival, attenuating progression of disease, improving functional capacity, and improving health-related quality of life (HRQL). Although there are multiple HRQL instruments that are psychometrically valid, concerns exist on the ability to reliably measure HRQL concepts. Nevertheless, there has been an emphasis on improving HRQL and thus novel therapies and clinical trials have included HRQL assessment routinely. Nonpharmacologic interventions have made a greater impact on HRQL, including the use of transcutaneous aortic valve replacement, left ventricular assist devices, and cardiac resynchronization devices. Pharmacologic therapies have resulted in modest improvements in HRQL and these improvements are often not clinically meaningful to the patient and not lasting beyond 6months. As novel therapies are developed for CHF patients, researchers must: (a) identify mechanisms that may meaningfully improve HRQL, (b) develop better instruments to measure HRQL, and (c) target the right population with enough impairment in their sense of well-being to enable an intervention to work. The recent publication of the Food and Drug Administration Draft Guidance for Use of Patient-Reported Outcome measures in clinical trials has served as the foundation for more robust trial design using these HRQL measures.

Application of Receiver Operating Characteristic Analysis to Refine the Prediction of Potential Digoxin Drug Interactions

In the 2012 Food and Drug Administration (FDA) draft guidance on drug-drug interactions (DDIs), a new molecular entity that inhibits P-glycoprotein (P-gp) may need a clinical DDI study with a P-gp substrate such as digoxin when the maximum concentration of inhibitor at steady state divided by IC₅₀ ([I₁]/IC₅₀) is ≥0.1 or concentration of inhibitor based on highest approved dose dissolved in 250 ml divide by IC₅₀ ([I₂]/IC₅₀) is ≥10. In this article, refined criteria are presented, determined by receiver operating characteristic analysis, using IC₅₀ values generated by 23 laboratories. P-gp probe substrates were digoxin for polarized cell-lines and N-methyl quinidine or vinblastine for P-gp overexpressed vesicles. Inhibition of probe substrate transport was evaluated using 15 known P-gp inhibitors. Importantly, the criteria derived in this article take into account variability in IC₅₀ values. Moreover, they are statistically derived based on the highest degree of accuracy in predicting true positive and true negative digoxin DDI results. The refined criteria of [I₁]/IC₅₀ ≥ 0.03 and [I₂]/IC₅₀ ≥ 45 and FDA criteria were applied to a test set of 101 in vitro-in vivo digoxin DDI pairs collated from the literature. The number of false negatives (none predicted but DDI observed) were similar, 10 and 12%, whereas the number of false positives (DDI predicted but not observed) substantially decreased from 51 to 40%, relative to the FDA criteria. On the basis of estimated overall variability in IC₅₀ values, a theoretical 95% confidence interval calculation was developed for single laboratory IC₅₀ values, translating into a range of [I₁]/IC₅₀ and [I₂]/IC₅₀ values. The extent by which this range falls above the criteria is a measure of risk associated with the decision, attributable to variability in IC₅₀ values.

Q&amp;A: Rajeshwari Sridhara, Robert Temple on Trial Design

Abstract Rajeshwari Sridhara, PhD, and Robert Temple, MD, who played lead roles in developing the U.S. Food and Drug Administration's draft guidance on enrichment strategies and adaptive design for clinical trials, talk about tends in trial design for oncology drugs.

Investigations on non‐inferiority—the Food and Drug Administration draft guidance on treatments for nosocomial pneumonia as a case for exact tests for binomial proportions

This paper addresses statistical issues in non-inferiority trials where the primary outcome is a fatal event. The investigations are inspired by a recent Food and Drug Administration (FDA) draft guideline on treatments for nosocomial pneumonia. The non-inferiority margin suggested in this guideline for the endpoint all-cause mortality is defined on different distance measures (rate difference and odds ratio) and is discontinuous. Furthermore, the margin enables considerable power for the statistical proof of non-inferiority at alternatives that might be regarded as clinically unacceptable, that is, even if the experimental treatment is harmful as compared with the control. We investigated the appropriateness of the proposed non-inferiority margin as well as the performance of possible test statistics to be used for the analysis. A continuous variant of the margin proposed in the FDA guideline together with the unconditional exact test according to Barnard showed favorable characteristics with respect to type I error rate control and power. To prevent harmful new treatments from being declared as non-inferior, we propose to add a 'second hurdle'. We discuss examples and explore power characteristics when requiring both statistical significance and overcoming the second hurdle.

Statistical considerations in biosimilar clinical efficacy trials with asymmetrical margins

Development of biosimilars to innovative therapeutic biologics promises reduction of healthcare cost and therefore will provide patients worldwide greater access to effective treatments. Because of the differences in raw materials or manufacturing processes, 'equivalence' of bioavailability between a biosimilar and the reference biologic is generally regarded as insufficient, and thus, clinical trials providing efficacy and safety data are often required by regulatory agencies. The traditional non-inferiority trial design may not be accepted for establishing biosimilarity in order to avoid superior efficacy with additional safety (e.g., immunogenicity) risks. On the other hand, the bioequivalence trial design, which is used in the generic paradigm for the evaluation of bioavailability of generic chemical drugs, is not appropriate for evaluating clinical efficacy because the equivalence margins are generally too wide and not justified on statistical or clinical grounds. Motivated by the World Health Organization guideline and the newly released Food and Drug Administration draft guideline on biosimilars, we propose a biosimilarity trial design for evaluating clinical efficacy. The design uses a non-inferiority margin and an asymmetrical non-superiority margin for statistical inference. The independent choice of both margins provides the scientific foundation for drawing clinical efficacy conclusions while maintaining the logical consistency of the inference. The design also has a higher statistical power than a naïve equivalence trial design.

Studies in rodents with the dipeptidyl peptidase‐4 inhibitor vildagliptin to evaluate possible drug‐induced pancreatic histological changes that are predictive of pancreatitis and cancer development in man

The present report summarizes rodent studies with vildagliptin, relevant to predicting pancreatitis or pancreatic cancer in man. As part of the regulatory development program for vildagliptin, a rodent toxicity program included two 104-week rodent (mouse and rat) carcinogenicity studies that were conducted according to guidelines assigned in Food and Drug Administration's Draft Guidance for Industry. Vildagliptin exposure in animals was evaluated for its effects on endocrine and exocrine pancreas. Two-year carcinogenicity studies were conducted in rats at oral doses up to 900 mg/kg (approximately 200 times the human exposure at the maximum recommended dose) and in mice at oral doses up to 1000 mg/kg (up to 240 times the human exposure at the maximum recommended dose). The results from these studies show the expected preservation and growth of the endocrine β-cells with no significant findings in the exocrine acinar pancreas. There was no evidence of inflammatory infiltrates characteristic of pancreatitis, no palpable mass detection based on gross examination or any microscopic findings indicative of pancreatic islet cell (endocrine), acinar cell (exocrine) or ductal (exocrine) neoplasia in rat or mouse. Evaluation of vildagliptin in 2-year preclinical carcinogenicity studies in both rats and mice indicates that while vildagliptin results in pharmacological benefits to the endocrine pancreas, this was not associated with any evidence of pancreatitis, pancreatic islet cell, acinar cell or ductal neoplasia. These data predict no increased risk of pancreatic cancer in man.

Paradigms for adaptive statistical information designs: practical experiences and strategies

In the last decade or so, interest in adaptive design clinical trials has gradually been directed towards their use in regulatory submissions by pharmaceutical drug sponsors to evaluate investigational new drugs. Methodological advances of adaptive designs are abundant in the statistical literature since the 1970s. The adaptive design paradigm has been enthusiastically perceived to increase the efficiency and to be more cost-effective than the fixed design paradigm for drug development. Much interest in adaptive designs is in those studies with two-stages, where stage 1 is exploratory and stage 2 depends upon stage 1 results, but where the data of both stages will be combined to yield statistical evidence for use as that of a pivotal registration trial. It was not until the recent release of the US Food and Drug Administration Draft Guidance for Industry on Adaptive Design Clinical Trials for Drugs and Biologics (2010) that the boundaries of flexibility for adaptive designs were specifically considered for regulatory purposes, including what are exploratory goals, and what are the goals of adequate and well-controlled (A&WC) trials (2002). The guidance carefully described these distinctions in an attempt to minimize the confusion between the goals of preliminary learning phases of drug development, which are inherently substantially uncertain, and the definitive inference-based phases of drug development. In this paper, in addition to discussing some aspects of adaptive designs in a confirmatory study setting, we underscore the value of adaptive designs when used in exploratory trials to improve planning of subsequent A&WC trials. One type of adaptation that is receiving attention is the re-estimation of the sample size during the course of the trial. We refer to this type of adaptation as an adaptive statistical information design. Specifically, a case example is used to illustrate how challenging it is to plan a confirmatory adaptive statistical information design. We highlight the substantial risk of planning the sample size for confirmatory trials when information is very uninformative and stipulate the advantages of adaptive statistical information designs for planning exploratory trials. Practical experiences and strategies as lessons learned from more recent adaptive design proposals will be discussed to pinpoint the improved utilities of adaptive design clinical trials and their potential to increase the chance of a successful drug development.

A Collaborative Model for Endpoint Development for Acute Bacterial Skin and Skin Structure Infections and Community-Acquired Bacterial Pneumonia

Two important diseases in need of new antibacterial drugs are acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP). These are common infections in the United States, with millions of patients treated annually. The identification of well-defined and reliable efficacy outcome measures for ABSSSI and CABP would greatly assist in clinical trials of new antibacterial drugs to treat the 2 diseases. With a clear clinical and regulatory need for outcome measures for ABSSSI and CABP, we approached the Biomarkers Consortium of the Foundation for the National Institutes of Health about assembling a project team. In this issue of Clinical Infectious Diseases, the project team of the Biomarkers Consortium of the Foundation for the National Institutes of Health (FNIH PT), as part of their ongoing work, provides a summary of data reviews, opinions, and recommendations for primary efficacy outcome measures for ABSSSI and CABP that will support development of new antibacterial drugs [1]. Additional work is planned to further improve and refine outcome measures. The FNIH PT brought together a wide range of experts in infectious diseases, statistical sciences, and clinical trials research from the academic research community, biopharmaceutical companies, and government. A unique perspective of the FNIH PT was the retrospective evaluation of outcome measures in data from various clinical trials of biopharmaceutical sponsors. The enormous research value in evaluating these data within a single collaborative project is reflected in the work of the FNIH PT and its presentation in this issue of Clinical Infectious Diseases. An especially important contribution of the data evaluation by the FNIH PT is the public access that it provides in the form of documents submitted in response to each of the Food and Drug Administration draft guidance documents for ABSSSI and CABP [2,3]. The review of the historical literature,

Implications of the New Food and Drug Administration Draft Guidance on Human Factors Engineering for Diabetes Device Manufacturers

This article discusses the implications of the new Food and Drug Administration's draft guidance on human factors and usability engineering for the development of diabetes-related devices. Important considerations include the challenge of identifying users, when the user population is so dramatically broad, and the challenge of identifying use environments when the same can be said for use environments. Another important consideration is that diabetes-related devices, unlike many other medical devices, are used constantly as part of the user's lifestyle--adding complexity to the focus on human factors and ease of use emphasized by the draft guidance.