How do you approach biomarker identification for a novel therapeutic in its early stages?

When embarking on biomarker identification, our initial step involves a thorough assessment of the therapeutic's mechanism of action and the disease pathophysiology. We then employ a multi-faceted strategy, often starting with bioinformatics analyses of publicly available or client-provided 'omics' data to pinpoint potential protein targets. Subsequent validation using our extensive IHC capabilities on diverse tissue cohorts allows us to establish analytical feasibility and preliminary clinical relevance.

What considerations are critical when developing an IHC-based CDx versus a nucleic acid-based one?

Developing an IHC-based CDx requires a unique set of considerations compared to nucleic acid tests. While both demand analytical rigor, IHC focuses on protein expression and localization within tissue architecture, which can directly reflect drug targets or pathways. Critical factors include antibody specificity, consistent tissue processing, standardized staining protocols, and the development of robust, objective scoring algorithms, often involving digital pathology for quantitative assessment.

What is your strategy for managing clinical sample variability during CDx development?

Managing clinical sample variability is paramount for CDx development. Our strategy involves establishing stringent sample collection, processing, and storage protocols to minimize pre-analytical variables. During assay development, we employ diverse sample sets to ensure robustness across different tissue types and preservation methods. For clinical validation, we utilize large, well-characterized patient cohorts, and our advanced digital pathology tools help normalize and standardize data analysis, mitigating inter-sample differences.

What kind of post-market support do you offer for your developed CDx products?

Our commitment to our clients extends beyond regulatory approval. For post-market support, we assist with establishing robust quality management systems for routine production, conduct post-market surveillance activities to monitor assay performance in real-world settings, and manage any required regulatory updates or variations. We also offer ongoing technical support and training for laboratories utilizing our CDx products, ensuring continued high-quality performance and patient benefit.

Companion Diagnostics (CDx) Development Service

As a leader in the development and commercialization of in vitro diagnostic (IVD) tests, Creative Biolabs offers specialized immunohistochemistry (IHC)-based companion diagnostic (CDx) development services. Our strength lies in transforming complex biomarker detection into precise, quantitative assays. We empower our clients by accelerating their therapeutic programs, ensuring therapies reach the right patients, and enhancing clinical outcomes with our robust and reliable CDx solutions.

Introduction to CDx

A CDx assay, as guided by regulatory bodies, constitutes an IVD device providing information absolutely essential for the safe and effective use of its corresponding therapeutic product. Its utility becomes paramount when a drug or biologic is designed to target a specific genetic or biological element not uniformly present across all patients sharing a particular disease. Consequently, these precise tests serve to identify individuals most likely to achieve a therapeutic response, while simultaneously distinguishing patients at differing risk levels for specific adverse side effects.

The technical methodologies employed for CDx tests are diverse, encompassing sophisticated techniques such as Polymerase Chain Reaction (PCR), Reverse Transcription PCR (RT-PCR), gene expression arrays, Next-Generation Sequencing (NGS), Fluorescent In Situ Hybridization (FISH), mass spectrometry, and IHC, among others. The proliferation of targeted therapies over recent decades has undeniably fueled a substantial and continuous increase in the demand for sophisticated CDx solutions.

Fig.1 Clinical regulatory frameworks for CDx. (Kang, et al., 2023) Fig.1 Necessity to strengthen current clinical regulatory frameworks for CDx.¹

CDx Based on IHC

Traditionally, IHC has served primarily as a diagnostic tool, providing various "special stains" for the identification and classification of cells and tumors within formalin-fixed paraffin-embedded (FFPE) tissues. Given its ability to demonstrate both the presence and cellular localization of a protein target, IHC is theoretically well-suited as a foundation for CDx. When IHC is applied in a CDx context, its role inherently shifts from a qualitative stain to a quantitative assay. Consequently, the critical inquiry evolves from simply detecting the presence of a target protein ("positive stain") to precisely quantifying its expression level. Any modification to the parameters and conditions of an IHC-based CDx, such as reagents, protocol, or scoring methodologies, can directly impact its clinical sensitivity and subsequent test results.

CDx Development Services Provided by Creative Biolabs

Creative Biolabs offers CDx development services based on IHC method to detect protein-based biomarkers. We are uniquely placed to partner with clients throughout the entire process of CDx development - from the fundamental research and discovery phase, through the conduct of clinical trials and the manufacturing of test kits, to the patient sample testing. We offer services including but not limited to:

Biomarker assay development
Analytical validation
Clinical validation
Kit development
Regulatory support/submissions
cGMP manufacturing
Project management
Commercialization

We focus on a wide spectrum of protein-based biomarkers that identify or track disease presence and progression, covering a variety of multiple disease areas:

Allergy
Autoimmune diseases
Cancer/tumor
Infectious diseases
Neurodegenerative diseases
Metabolic diseases

CDx Development Process

Our streamlined CDx development process is meticulously designed to ensure precision, compliance, and efficiency:

Step 1

Biomarker Identification & Analytical Feasibility

We initiate with thorough biomarker research, assessing potential protein targets for their relevance and analytical viability using advanced IHC techniques on relevant tissue samples.

Step 2

Assay Development & Optimization

Our experts design and meticulously optimize the IHC assay, determining optimal antibody concentrations, staining protocols, and detection systems to achieve high specificity and sensitivity.

Step 3

Analytical Validation

Rigorous validation confirms the assay's performance characteristics, including sensitivity, specificity, accuracy, precision, reproducibility, and robustness across various conditions.

Step 4

Clinical Development & Validation

We integrate the CDx assay into clinical trials, designing studies to validate its clinical utility in stratifying patients based on therapeutic response or risk profiles. This includes establishing optimal scoring criteria and cut-off values.

Step 5

Regulatory Strategy & Submission Support

Our dedicated regulatory team provides comprehensive guidance and support for submissions to key regulatory bodies, and other global agencies, ensuring compliance at every step.

Step 6

Manufacturing & Quality Control

We establish robust manufacturing processes and implement stringent quality control measures to ensure consistent production of high-quality CDx kits, adhering to international standards.

Step 7

Commercialization & Post-Market Support

We assist with commercialization strategies, including training and support for diagnostic laboratories, and provide ongoing post-market surveillance to monitor assay performance and gather real-world data.

Features of Our Services

Quantitative IHC Expertise

Specialization in IHC goes beyond standard staining. We deliver a precise quantitative assessment of protein biomarkers, crucial for accurate patient eligibility and therapeutic response. This rigorous approach ensures highly reliable and reproducible clinical results.

Streamlined Regulatory Compliance

Navigating global regulatory landscapes is complex. Comprehensive regulatory strategy and submission support is provided, from early engagement with authorities through final approvals. This expertise significantly reduces risks and accelerates market access.

Integrated Co-Development

An integrated co-development model ensures seamless alignment of CDx development with therapeutic clinical trials. This collaborative approach minimizes timelines, optimizes resource allocation, and synchronizes the diagnostic tool perfectly with the drug's intended use, boosting success rates.

Unwavering Quality Assurance

Commitment to quality is paramount. All development activities adhere to stringent CLIA and CAP standards, alongside global quality management systems. This meticulous attention to detail ensures the analytical validity and clinical utility of every CDx, building confidence in diagnostic performance.

Q&A

Q: How do you approach biomarker identification for a novel therapeutic in its early stages?

A: When embarking on biomarker identification, our initial step involves a thorough assessment of the therapeutic's mechanism of action and the disease pathophysiology. We then employ a multi-faceted strategy, often starting with bioinformatics analyses of publicly available or client-provided 'omics' data to pinpoint potential protein targets. Subsequent validation using our extensive IHC capabilities on diverse tissue cohorts allows us to establish analytical feasibility and preliminary clinical relevance.
Q: What considerations are critical when developing an IHC-based CDx versus a nucleic acid-based one?

A: Developing an IHC-based CDx requires a unique set of considerations compared to nucleic acid tests. While both demand analytical rigor, IHC focuses on protein expression and localization within tissue architecture, which can directly reflect drug targets or pathways. Critical factors include antibody specificity, consistent tissue processing, standardized staining protocols, and the development of robust, objective scoring algorithms, often involving digital pathology for quantitative assessment.
Q: What is your strategy for managing clinical sample variability during CDx development?

A: Managing clinical sample variability is paramount for CDx development. Our strategy involves establishing stringent sample collection, processing, and storage protocols to minimize pre-analytical variables. During assay development, we employ diverse sample sets to ensure robustness across different tissue types and preservation methods. For clinical validation, we utilize large, well-characterized patient cohorts, and our advanced digital pathology tools help normalize and standardize data analysis, mitigating inter-sample differences.
Q: What kind of post-market support do you offer for your developed CDx products?

A: Our commitment to our clients extends beyond regulatory approval. For post-market support, we assist with establishing robust quality management systems for routine production, conduct post-market surveillance activities to monitor assay performance in real-world settings, and manage any required regulatory updates or variations. We also offer ongoing technical support and training for laboratories utilizing our CDx products, ensuring continued high-quality performance and patient benefit.

The CDx development services can be provided for pharmaceuticals in both preclinical and clinical development, as well as for pharmaceuticals that are already on the market. We offer our customers individual diagnostic solutions to implement the concept of personalized medicine. Contact us to discuss your project and experience the great value of our services.

Reference

Kang, Su Lim, et al. "Necessity of strengthening the current clinical regulatory for companion diagnostics: An institutional comparison of the FDA, EMA, and MFDS." Molecular Therapy-Methods & Clinical Development 30 (2023): 447-458. Distributed under Open Access license CC BY 4.0, without modification.

For Research Use Only.

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