ResearchPad - tutorial Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Regulatory Affairs 101: Introduction to Expedited Regulatory Pathways]]> Developing a novel drug, including discovery, nonclinical toxicology studies, initial clinical trials, and thorough pivotal studies, may take many years. Once an applicant has generated this comprehensive body of data, the final step prior to regulatory approval is Health Authority review of the marketing authorization application. Review by regulatory authorities to evaluate whether the data support a positive benefit/risk profile takes many months, adding additional time before patients may access therapy. In this paper, we discuss the various opportunities the US Food and Drug Administration and the European Medicines Agency offer to expedite the drug development and regulatory approval timelines for drugs intended to treat serious diseases and unmet medical needs.

<![CDATA[Machine Learning in Drug Discovery and Development Part 1: A Primer]]>

Artificial intelligence, in particular machine learning (ML), has emerged as a key promising pillar to overcome the high failure rate in drug development. Here, we present a primer on the ML algorithms most commonly used in drug discovery and development. We also list possible data sources, describe good practices for ML model development and validation, and share a reproducible example. A companion article will summarize applications of ML in drug discovery, drug development, and postapproval phase.

<![CDATA[Pharmacokinetic variability due to environmental differences]]>

This tutorial describes sources of pharmacokinetic variability that are not obviously linked to genetic differences. The sources of variability are therefore described as environmental. The major quantitative sources of environmental variability are body size (including body composition), maturation and organ function. Size should be considered in all patients. Maturation is mainly relevant to neonates and infants less than 2 years of age. Renal function is the most important predictable source of variability due to differences in organ function.

<![CDATA[The stable isotope method for determining absolute bioavailability]]>

The bioavailability of a drug is usually assessed in healthy subjects. However, it is reasonable to expect that significant alterations in bioavailability may occur in actual patients with different diseases or in individuals belonging to special populations. Relatively few studies have been conducted to examine this possibility. The stable isotope method is well suited to compare absolute bioavailability in patients and healthy subjects. Studies in which this method was used indicate that significant changes in the bioavailability of some drugs are particularly likely in patients with advanced liver disease and in those whose splanchnic blood flow is reduced. The expectation is that bioavailability in neonates, children, and pregnant women may also differ from that in non-pregnant adults.

<![CDATA[Selection of In Vivo Predictive Dissolution Media Using Drug Substance and Physiological Properties]]>

The rate and extent of drug dissolution in the gastrointestinal (GI) tract are highly dependent upon drug physicochemical properties and GI fluid properties. Biorelevant dissolution media (BDM), which aim to facilitate in vitro prediction of in vivo dissolution performance, have evolved with our understanding of GI physiology. However, BDM with a variety of properties and compositions are available, making the choice of dissolution medium challenging. In this tutorial, we describe a simple and quantitative methodology for selecting practical, yet physiologically relevant BDM representative of fasted humans for evaluating dissolution of immediate release formulations. Specifically, this methodology describes selection of pH, buffer species, and concentration and evaluates the importance of including bile salts and phospholipids in the BDM based upon drug substance log D, pKa, and intrinsic solubility. The methodology is based upon a mechanistic understanding of how three main factors affect dissolution, including (1) drug ionization at gastrointestinal pH, (2) alteration of surface pH by charged drug species, and (3) drug solubilization in mixed lipidic aggregates comprising bile salts and phospholipids. Assessment of this methodology through testing and comparison with literature reports showed that the recommendations correctly identified when a biorelevant buffer capacity or the addition of bile salts and phospholipids to the medium would appreciably change the drug dissolution profile. This methodology can enable informed decisions about when a time, complexity, and/or cost-saving buffer is expected to lead to physiologically meaningful in vitro dissolution testing, versus when a more complex buffer would be required.

Electronic supplementary material

The online version of this article (10.1208/s12248-020-0417-8) contains supplementary material, which is available to authorized users.

<![CDATA[A primer on resolving the nanoscale structure of the plasma membrane with light and electron microscopy]]>

Taraska reviews the imaging methods that are being used to understand the structure of the plasma membrane at the molecular level.

<![CDATA[Speech-Language Disorders in 22q11.2 Deletion Syndrome: Best Practices for Diagnosis and Management]]>


Speech and language disorders are hallmark features of 22q11.2 deletion syndrome (22qDS). Learning disabilities, cognitive deficits, palate abnormalities, velopharyngeal dysfunction, behavioral differences, and various medical and psychiatric conditions are also major features of this syndrome. The goal of this document is to summarize the state of the art of current clinical and scientific knowledge regarding 22qDS for speech-language pathologists (SLPs) and provide recommendations for clinical management.


Best practices for management of individuals with 22qDS were developed by consensus of an expert international group of SLPs and researchers with expertise in 22qDS. These care recommendations are based on the authors' research, clinical experience, and literature review.


This document describes the features of 22qDS as well as evaluation procedures, treatment protocols, and associated management recommendations for SLPs for the often complex communication disorders present in this population.


Early diagnosis and appropriate management of speech-language disorders in 22qDS is essential to optimize outcomes and to minimize the long-term effects of communication impairments. Knowledge of this diagnosis also allows anticipatory care and guidance regarding associated features for families, health care, and educational professionals.

<![CDATA[How to review a surgical paper: a guide for junior referees]]>

Reviewing a surgical manuscript is not an easy task, and there is no formal training available for young referees in the early stage of their careers. Accepting a peer review assignment represents a personal honor for the invited referee and a fundamental ethical responsibility towards the scientific community. Designated reviewers must be accomplished and knowledgeable in the area of the respective topic of investigation. More importantly, they must be aware and cognizant about the cardinal ethical responsibility and stewardship for ensuring the preservation of scientific knowledge of unbiased and unquestionable accuracy in the published literature. Accepting a review assignment should never be taken lightly or considered a simple task, regardless of the reviewer’s level of seniority and expertise. Indeed, there are multiple challenges, difficulties, and ‘hidden dangers’ that jeopardize the completion of a high-quality review, particularly in the hands of less experienced or novice reviewers. The present article was designed to provide a brief, concise, and practical guide on how to review manuscripts for the ‘junior referee’ in the field of surgery.

<![CDATA[The Many Flavors of Model‐Based Meta‐Analysis: Part I—Introduction and Landmark Data]]>

Meta‐analysis is an increasingly important aspect of drug development as companies look to benchmark their own compounds with the competition. There is scope to carry out a wide range of analyses addressing key research questions from preclinical through to postregistration. This set of tutorials will take the reader through key model‐based meta‐analysis (MBMA) methods with this first installment providing a general introduction before concentrating on classical and Bayesian methods for landmark data.

<![CDATA[Patenting inventions arising from biological research]]>

This article describes the steps involved and the considerations needed for successful granting of a patent for biological ideas and technologies.

<![CDATA[Optimal strategies to consider when peer reviewing a systematic review and meta-analysis]]>

Systematic reviews are popular. A recent estimate indicates that 11 new systematic reviews are published daily. Nevertheless, evidence indicates that the quality of reporting of systematic reviews is not optimal. One likely reason is that the authors’ reports have received inadequate peer review. There are now many different types of systematic reviews and peer reviewing them can be enhanced by using a reporting guideline to supplement whatever template the journal editors have asked you, as a peer reviewer, to use. Additionally, keeping up with the current literature, whether as a content expert or being aware of advances in systematic review methods is likely be make for a more comprehensive and effective peer review. Providing a brief summary of what the systematic review has reported is an important first step in the peer review process (and not performed frequently enough). At its core, it provides the authors with some sense of what the peer reviewer believes was performed (Methods) and found (Results). Importantly, it also provides clarity regarding any potential problems in the methods, including statistical approaches for meta-analysis, results, and interpretation of the systematic review, for which the peer reviewer can seek explanations from the authors; these clarifications are best presented as questions to the authors.

<![CDATA[A guide to performing a peer review of randomised controlled trials]]>

Peer review of journal articles is an important step in the research process. Editors rely on the expertise of peer reviewers to properly assess submissions. Yet, peer review quality varies widely and few receive training or guidance in how to approach the task.

This paper describes some of the main steps that peer reviewers in general and, in particular, those performing reviewes of randomised controlled trials (RCT), can use when carrying out a review. It can be helpful to begin with a brief read to acquaint yourself with the study, followed by a detailed read and a careful check for flaws. These can be divided into ‘major’ (problems that must be resolved before publication can be considered) and ‘minor’ (suggested improvements that are discretionary) flaws. Being aware of the appropriate reporting checklist for the study being reviewed (such as CONSORT and its extensions for RCTs) can also be valuable.

Competing interests or prejudices might corrode the review, so ensuring transparency about them is important. Finally, ensuring that the paper’s strengths are acknowledged along with a dissection of the weaknesses provides balance and perspective to both authors and editors. Helpful reviews are constructive and improve the quality of the paper. The proper conduct of a peer review is the responsibility of all who accept the role.

<![CDATA[How to spot a statistical problem: advice for a non-statistical reviewer]]>

Statistical analyses presented in general medical journals are becoming increasingly sophisticated. BMC Medicine relies on subject reviewers to indicate when a statistical review is required. We consider this policy and provide guidance on when to recommend a manuscript for statistical evaluation. Indicators for statistical review include insufficient detail in methods or results, some common statistical issues and interpretation not based on the presented evidence. Reviewers are required to ensure that the manuscript is methodologically sound and clearly written. Within that context, they are expected to provide constructive feedback and opinion on the statistical design, analysis, presentation and interpretation. If reviewers lack the appropriate background to positively confirm the appropriateness of any of the manuscript’s statistical aspects, they are encouraged to recommend it for expert statistical review.

<![CDATA[Low‐event‐rate meta‐analyses of clinical trials: implementing good practices]]>

Meta‐analysis of clinical trials is a methodology to summarize information from a collection of trials about an intervention, in order to make informed inferences about that intervention. Random effects allow the target population outcomes to vary among trials. Since meta‐analysis is often an important element in helping shape public health policy, society depends on biostatisticians to help ensure that the methodology is sound. Yet when meta‐analysis involves randomized binomial trials with low event rates, the overwhelming majority of publications use methods currently not intended for such data. This statistical practice issue must be addressed. Proper methods exist, but they are rarely applied. This tutorial is devoted to estimating a well‐defined overall relative risk, via a patient‐weighted random‐effects method. We show what goes wrong with methods based on ‘inverse‐variance’ weights, which are almost universally used. To illustrate similarities and differences, we contrast our methods, inverse‐variance methods, and the published results (usually inverse‐variance) for 18 meta‐analyses from 13 Journal of the American Medical Association articles. We also consider the 2007 case of rosiglitazone (Avandia), where important public health issues were at stake, involving patient cardiovascular risk. The most widely used method would have reached a different conclusion. © 2016 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.