Skip to main content

ICH E4 Dose response information to support drug registration (CPMP/ICH/378/95)

 ICH E4 is a guideline titled "Dose-Response Information to Support Drug Registration" with the reference number CPMP/ICH/378/95. This guideline, developed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), provides recommendations and principles for collecting, analyzing, and presenting dose-response information as part of the drug registration process. Dose-response information is crucial for establishing the appropriate dosing regimen for a new drug. Here's an elaboration of ICH E4:


1. Purpose:

The primary purpose of ICH E4 is to guide the pharmaceutical industry and regulatory authorities on the generation and evaluation of dose-response data for new drugs. It aims to ensure that dose-response relationships are well-understood and support the safe and effective use of the drug.

2. Applicability:

ICH E4 is applicable to all phases of drug development, including preclinical and clinical studies, and it covers various types of drug products, including small molecules, biologics, and other therapeutic agents.

3. Key Considerations:

The guideline emphasizes several key considerations when evaluating dose-response information:

  • Determining the therapeutic range: Identifying the range of doses that provide optimal efficacy and an acceptable safety profile.
  • Characterizing the dose-response relationship: Understanding how the drug's effect varies with different doses.
  • Identifying the minimum effective dose (MED): Determining the lowest dose that produces a clinically meaningful effect.
  • Assessing the maximum tolerated dose (MTD): Identifying the highest dose that can be administered safely.
  • Evaluating dose-response trends: Analyzing the shape of the dose-response curve, including any plateau or saturation effects.
  • Assessing exposure-response relationships: Examining how drug exposure (e.g., plasma concentration) relates to clinical response.

4. Clinical Trial Design:

ICH E4 provides recommendations for the design of clinical trials aimed at assessing dose-response relationships. This includes considerations for dosing regimens, endpoints, and the selection of appropriate patient populations.

5. Data Analysis:

The guideline outlines principles for the analysis of dose-response data, including the use of appropriate statistical methods and graphical representations to characterize the relationship between dose and response.

6. Safety Considerations:

Safety assessments are integral to dose-response evaluations. The guideline emphasizes the importance of monitoring and evaluating adverse events and safety parameters across dose groups.

7. Extrapolation:

ICH E4 discusses the potential for extrapolating dose-response information from one population to another, such as from adult data to pediatric or geriatric populations, when justified and supported by scientific evidence.

8. Regulatory Submissions:

Dose-response information is a critical component of regulatory submissions, such as New Drug Applications (NDAs) or Marketing Authorization Applications (MAAs). The guideline provides guidance on the presentation of dose-response data in these submissions.

9. Risk-Benefit Assessment:

The guideline emphasizes that a comprehensive understanding of the dose-response relationship contributes to the assessment of the drug's risk-benefit profile.

10. Compliance:

- Pharmaceutical companies are expected to comply with ICH E4 to ensure that dose-response information is appropriately collected, analyzed, and presented in support of drug registration.


In summary, ICH E4 provides a framework for the collection and evaluation of dose-response information to support the registration of new drugs. Compliance with this guideline ensures that dose-response relationships are well-characterized, contributing to the safe and effective use of pharmaceutical products and informed regulatory decisions

Labels:

Popular posts from this blog

Ago2 Immunoprecipitation for RISC-siRNA Quantitation

 Ago2 (Argonaute 2) immunoprecipitation (IP) is a technique used to isolate RNA-induced silencing complexes (RISC) from cell lysates. This method allows for the specific enrichment of active RISC complexes bound to small interfering RNA (siRNA) or microRNA (miRNA) within cells. By isolating these complexes, researchers can then quantify the siRNA associated with Ago2, which is an essential step in determining the efficacy of RISC loading and siRNA activity. Here’s a detailed overview of how Ago2 immunoprecipitation is performed for RISC-siRNA quantitation: Steps in Ago2 Immunoprecipitation for RISC-siRNA Quantitation Cell Lysis and Preparation of Lysate : Sample Preparation : Collect cells that have been treated with siRNA, then wash them with cold phosphate-buffered saline (PBS) to remove extracellular contaminants. Lysis : Lyse the cells in a gentle, RNA-preserving lysis buffer that typically includes detergents (e.g., NP-40 or Triton X-100), protease inhibitors, and RNase inhibi...
Read more

Guideline on development and manufacture of lentiviral vectors (CHMP/BWP/2458/03)

The guideline with the reference number "CHMP/BWP/2458/03" pertains to the "Guideline on Development and Manufacture of Lentiviral Vectors." This guideline was developed by the Committee for Medicinal Products for Human Use (CHMP) and the Biotechnology Working Party (BWP) of the European Medicines Agency (EMA). It provides recommendations and regulatory guidance for the development and manufacture of lentiviral vectors, which are widely used in gene therapy and cell therapy applications. Here's an overview of the key points covered in this guideline: 1. Introduction: The guideline begins with an introduction highlighting the increasing importance of lentiviral vectors in advanced therapies and the need for guidance on their development and manufacture. 2. Scope: It defines the scope of the guideline, which covers the development and manufacture of lentiviral vectors intended for use in gene therapy and cell therapy products for human use. 3. Quality and Characte...
Read more

Stem-Loop PCR for siRNA

 Stem-loop PCR is a method often used for detecting and quantifying small RNAs, such as siRNA or miRNA, which are typically difficult to amplify directly due to their short lengths. The method involves the design of a stem-loop reverse transcription (RT) primer, which enhances specificity and stability of the short RNA during the RT-PCR process, allowing for sensitive detection and quantification of the siRNA. Here’s a detailed guide to how stem-loop PCR can be applied to siRNA detection: Key Steps in Stem-Loop PCR for siRNA Designing the Stem-Loop RT Primer : Structure : The stem-loop RT primer consists of a loop region flanked by complementary sequences on either side (the "stem"), which will fold back on itself to form a hairpin structure. Specific Binding Region : A short sequence complementary to the 3’ end of the siRNA is added at the end of the stem-loop primer to ensure specific binding to the siRNA target. Stabilization : The loop structure helps prevent primer-dimer...
Read more

FDA Guidance on Studying Multiple Versions of Cellular or Gene Therapy Products in Early-Phase Clinical Trials

 The purpose of this guidance is to offer advice to sponsors interested in conducting early-phase clinical trials for a single disease involving multiple variations of a cellular or gene therapy product. Sponsors aim to gather preliminary safety and efficacy data for these product variations within a single clinical trial. It's important to note that even though multiple product versions are studied together, each version is distinct and typically requires a separate investigational new drug application (IND) submission to the FDA. The primary goal of these early-phase clinical studies is to inform decisions about which product version(s) should be advanced for further development in later-phase trials. As such, these studies are not designed to provide the main evidence of effectiveness needed for a marketing application. They are generally not statistically powered to demonstrate a significant difference in efficacy between the different study arms. In this guidance, the FDA prov...
Read more

Stem loop RT-PCR for Detection of siRNA in Animal Tissues

Step Loop RT-PCR for Detection of Small Interfering RNA (siRNA) The recent publications described a novel used the novel method for the detection of siRNAs using a TaqMan®-based approach. This approach utilizes similar strategy that has been used for microRNA detection. The approach is illustrated in below.  In brief, the RT step occurs in the presence of a stem-loop RT primer that is complementary to the last 6–10 bases of the 3′ end of the antisense strand of the target siRNA. The stem-loop primer contains an additional universal sequence at the 5′ end that facilitates a TaqMan-based detection strategy in the subsequent qPCR step. As in the case of microRNA, the forward primer for qPCR is sequence-specific for the target siRNA. For sequence compositions that yield a low predicted melting temperature (Tm), the forward primer is designed as a tailed primer to help increase Tm. Stem Loop PCR for SiRNA Detection Step 1: Preparation of liver and plasma samples for the quanti...
Read more