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Related Concept Videos

Clinical Trials: Overview01:11

Clinical Trials: Overview

Clinical development focuses on how the drug will interact with the human body and encompasses four key phases of clinical trials, each serving a specific purpose in assessing the safety and effectiveness of new drugs. These phases overlap and build upon one another. Phase I involves a small group of healthy volunteers (typically 20-80 individuals) or, in cases where significant toxicity is expected, patients with the targeted disease, such as cancer or AIDS. The volunteers are tested for...
Preclinical Development: Overview01:28

Preclinical Development: Overview

Preclinical development consists of a series of tests that ensure the safety and efficacy of a new therapeutic compound before it is tested in humans. There are four main phases to this process. First, safety pharmacology tests are conducted to ensure the drug does not produce any acutely harmful effects. These tests examine parameters such as bronchoconstriction, cardiac dysrhythmias, blood pressure changes, and ataxia. Next, preliminary toxicological testing is performed to determine the...
Clinically Relevant Drug Product Specifications: Methods of Establishment01:29

Clinically Relevant Drug Product Specifications: Methods of Establishment

Product specifications define the acceptable quality of a pharmaceutical product by ensuring identity, purity, potency, and strength. These specifications serve as benchmarks during development, manufacturing, and post-approval quality control. Clinically relevant specifications are particularly important because they directly relate to a drug's safety and efficacy in clinical use.Dissolution studies are critical biopharmaceutic tools that link in vitro behavior to in vivo performance. They...
Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu01:29

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu

Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
Pharmaceutical Alternatives: Polymorphic Form-Related and Particle Size-Related Therapeutic Nonequivalence01:27

Pharmaceutical Alternatives: Polymorphic Form-Related and Particle Size-Related Therapeutic Nonequivalence

Changes in polymorphic forms can significantly influence the bioavailability of poorly soluble drugs. Although the FDA defines pharmaceutical equivalence based on having the same active ingredient, dosage form, and route of administration, it does not automatically disqualify products with different polymorphic forms. This means two products with different polymorphs can still be deemed pharmaceutically equivalent. However, polymorphic differences can affect properties like wettability,...
Bioequivalence of Drugs: Drugs with Multiple Indications01:09

Bioequivalence of Drugs: Drugs with Multiple Indications

The concept of therapeutic equivalence (TE) in drugs with multiple indications is complex. A generic drug may be therapeutically equivalent to a brand-name product for one specific indication, but this doesn't necessarily mean it's equivalent for all other indications. Evidence of TE in one patient group and bioequivalence shown in healthy volunteers can support—but not confirm—TE for other indications. However, definitive proof requires individual clinical studies for each indication due to...

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Candidate Gene Testing in Clinical Cohort Studies with Multiplexed Genotyping and Mass Spectrometry
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Key multiplicity issues in clinical drug development.

Alex Dmitrienko1, Ralph B D'Agostino, Mohammad F Huque

  • 1Quintiles, Inc., Durham, NC, 27703, USA. alex.dmitrienko@quintiles.com

Statistics in Medicine
|October 10, 2012
PubMed
Summary

Novel methods now address complex multiplicity issues in Phase III clinical trials, including multiple endpoints and dose levels. This review covers error rates, testing procedures, and recent advances like gatekeeping for drug development.

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Area of Science:

  • Biostatistics
  • Clinical Trial Design
  • Pharmaceutical Research

Background:

  • Confirmatory Phase III clinical trials face complex multiplicity problems.
  • These include single sources (multiple endpoints, dose-placebo contrasts) and multiple sources (multiple objectives, doses, populations).

Purpose of the Study:

  • To review fundamental concepts in defining and solving multiplicity problems.
  • To introduce main classes of multiple testing procedures used in clinical trials.
  • To present recent advances in multiplicity research, including gatekeeping procedures.

Main Methods:

  • Review of error rate definitions.
  • Introduction of nonparametric, semiparametric, and parametric multiple testing procedures.
  • Discussion of gatekeeping procedures for multiple objective sets.

Main Results:

  • Progress in addressing complex multiplicity in clinical trials.
  • Illustration of concepts and methods with real clinical trial case studies.
  • Discussion of software implementation for multiple testing and gatekeeping.

Conclusions:

  • Advanced methods are crucial for managing multiplicity in modern clinical trials.
  • Gatekeeping procedures offer solutions for trials with multiple sets of objectives.
  • Practical implementation is supported by available software.