Biomarkers Strategies and Implementation for Drug Development (Regulatory Webcast Summary)

Flagship Biosciences recently hosted a webcast on Biomarkers: Strategies and Implementation, and Drug Development. Introduced by our COO Meredith James, we were pleased to have our colleague Suzana Corritori, MD, PhD, MSc present her thoughts on a strategic approach to biomarkers and the FDA’s regulatory process.

Biomarkers are important tools for successful biopharmaceutical-targeted drug development and regulatory approval and can support precision drug targeting in each phase of development. As such, biomarkers are increasingly used to characterize disease, monitor treatment performance, enrich responsive patient enrollment in clinical trials, and support regulatory process and labeling.

Biomarker assay development should start early in the drug development cycle, with timing crafted for individual development phases. This co-development process can be a particular challenge for emerging biotech companies with limited funds and resources and requires decisions to be made on how to optimize and advance biomarker assay development to support preclinical or clinical development.

Other critical consideration includes when to transition the assay into companion diagnostic development, which comes with additional regulatory requirements. The purpose of the webinar was to provide practical considerations and guidance to navigate through successful biomarker strategy implementation into multi-faceted drug development and regulatory approval.

Flagship recently expanded its services to include regulatory and drug development support at all phases of development. In addition, at each step in the process, our team provides contextual data, including tumor, stoma, and immune characterization, to ensure the right patients as well as the most informative endpoints are obtained.

Due to the objective nature of image analysis and the large volume of data that is generated, pathology interpretations are unbiased and cut-point evaluation can be adapted at any stage to mitigate risk.

Slide title topics covered in the complete presentation include:

  • Flagship Regulatory and Drug Development Support
  • Topic Overview
  • Biomarkers, Endpoints and other Tools (BEST) glossary FDA Definition of a Biomarker
  • Biomarkers Can Contribute to Success In Each Phase of Targeted Drug Development
  • Biomarkers and Probability of Success
  • Desired Biomarker Attributes
  • Use of Biomarkers in Drug Development
  • Biomarkers Categories in the Context of Intended Use
  • Utility of Biomarkers as Surrogate Endpoints
  • Key Strategic Steps of Incorporation of Biomarkers in Clinical Trials
  • Regulatory Aspects of Integration of New Biomarkers in Drug Development
  • Biomarker Assays
  • Selection of a Fit-for-Purpose Biomarker Assay
  • Biomarker Assay Validation
  • Interrelated processes of analytical and clinical validation of the biomarker for its proposed context of use (COU)
  • Levels of Biomarker Assay Development/Validation Are Linked to Goals of Each Drug Development Phase
  • Master Clinical Study Protocols
  • Key Points to Consider for Basket and Umbrella Trials
  • Laboratory Developed Test (LDT)
  • Regulatory Labeling/Distribution of IVDs/CDx
  • Risk-Based Categories of IVDs
  • FDA Regulatory Approval Pathways for New IVDs
  • Flagship Assists Clients with Biomarker Assay/CDx Development Through Each Phase of Drug Development

Overview of Biomarkers, Endpoints, and other Tools and Biomarker Definition

Biomarkers assessments can be included in any phase of targeted drug development, and they can contribute to the success of drug development at any phase. They can serve as a molecular target for drug action or support the drug action. They can be part of input and pharmacodynamic response. They can help the evaluation of safety and they can serve for monitoring of important outcomes in the trial and in contributing to the overall characterization of the risk-benefit profile of the drug or therapeutic intervention. When they serve as surrogate study endpoints the related information becomes a part of product labeling.

Among the other factors, the probability of drug development success has been shown consistently to depend on the development and use of biomarkers and associated technologies, resulting in increased efficacy, improved safety, and more personalized treatment.

Dr. Corritori shared that as much as we would wish, there is no such a thing as ideal biomarker from a drug development perspective, however certain attributes of a biomarker are highly desired. For example, the biomarker should be part of the disease, either related to disease, burden, or disease spread and other characteristics like metastatic spread of tumors. Biomarkers should change in accordance with the clinical evolution, reflecting the status of disease, or the treatment, and be measured by a compounding laboratory assay that is robust, easily reproducible, and reliable. It should also be economically viable. It should be relatively inexpensive, and it should not add to the financial burden of the patient.

There are different biomarker categories related to the context of their intended use. A brief summary of the major biomarker categories includes diagnostic, prognostic, predictive, pharmacodynamic/response, monitoring, susceptibility/risk, and safety. All of these biomarkers can be used in research and drug development. For an extensive chart showing examples of each, view the recorded webinar.

Points to Consider for Successful Implementation of Biomarkers in Clinical Trials

Planning the use of biomarker is a data-driven, step-wise approach which is very similar to that used to assess the readiness of a new or established therapeutic for clinical evaluation.

To position successfully the implementation of biomarkers in clinical trials, several key points are to be considered.  First of all, the role of a given biomarker needs to be identified for a particular use. The key questions that need to be answered in this phase is whether the biomarker adequately supports the clinical drug evaluation in trials and is it ready to be used in trials.

Development and selection of a fit-for-purpose biomarker assay and lab vendor are critical in this process and requires careful coordination of available expertise, capabilities, and resources. If you are a mid-size or large pharma, this means that you carefully assess balance between in-house and outsourced activities, while selection of right vendor is critical factor of success for small, emerging companies. Flagship supports both small and large companies and we welcome you to contact us to learn more how our capabilities can support your programs. Analytical validation of the biomarker assay is specific within a context of use and you should make sure that this is adequate for the purpose and clinical trial setting. This can also include consideration about the best tissue matrix, ease of obtaining from patients and proper handling the samples as well as use of proper reagents for the assay in the context of physico-chemical characteristics of the biomarker. This process can progress to different levels depending on the phase of overall drug development for example, in early Phase clinical trials is often unnecessary to have fully validated biomarker test. This commonly comes important to support pivotal clinical trials.

Furthermore, depending on the context of use, the biomarker assessments will be incorporated in the  clinical study design in a different ways, from being exploratory, hypothesis-generating useful information through being integrated more substantially into study design testing the previously formulated hypothesis to potentially becoming integral to the study design, when typically  such biomarker is a study endpoint and its assessments must be done in real-time to allow for further progress of clinical study conduct.

Continuous data review and planning for further investigations, as warranted by prior clinical experience, will be subject to regulatory review and assessments, and eventually lead to considerations for companion diagnostic if integral for safe and effective use of the drug in clinical practice.

Regulatory Aspects of Biomarkers in Drug Development

From a regulatory perspective, there are two main regulatory pathways to integrate biomarkers in drug development. Subsequent clinical use and the potential development of biomarkers as an integral part of the drug approval process in a specific clinical indication depend on the type of regulatory pathway.

Drug developers may choose to use biomarkers, established or novel, as part of clinical trials to answer questions pertinent to a particular drug. For novel biomarkers, the drug developer is responsible for all aspects of the biomarker’s development. If new information suggests that the biomarker may be useful in other drug development programs, then the FDA may include the use of the biomarker in guidance or approved product labeling.

Biomarker Qualification Program (BQP)

Qualification through BQP is required for biomarkers that may be used in multiple drug development programs. Once qualified, a biomarker can be used under its qualified context of use (COU) during the development of any candidate drug. It is the biomarker and not the biomarker assay that is qualified in this program

The development of biomarkers supporting specific drug development programs is usually the responsibility of the sponsor. However, if new information suggests their utility in another drug development program, then the FDA may include their use in their regulatory guidance or approved product labeling. Each biomarker is qualified for a specific context of use, and important to note, it is the biomarker that is qualified in this process, not the assay.

Assay Acceptance and Validation

Assay acceptance criteria are also complex. They can be qualitative, semi-quantitative, or quantitative. The level of validation can also be exploratory or more advanced, still, as an in-house assay, and can go all the way to full validation. Important factors can include the variability of measurements and sources of validation, intent, and sample collection and processing, and the logistics of the process, as well as patient selection. Different drug development phases call for different levels of biomarker assay development or validation.

Feasibility, Validation, Phases, and Regulatory Submissions

At any phase of drug development, Flagship can help you to demonstrate feasibility, develop a prototype assay, and support analytical and clinical validation of the assay. We can prepare regulatory submissions, and even file with the agency and support additional commercial aspects. We can also help you to engage in continued dialogue with the agency based on a clear understanding of development strategy and applying that strategy in a stepwise, data driven process.

With the last slide of the presentation, Suzana covered how Flagship can help our clients through every phase of drug development including:

  • PHASE I: Demonstrate feasibility: Flagship can use existing CDx, RUO, or novel IHC/ISH assays along with our proprietary image analysis to develop solutions that accurately and consistently identify the biomarker(s) that are most critical to your therapeutic.
  • PHASE II: Develop prototype: Flagship will validate the appropriate tissue biomarker solution as a Lab Developed Test (LDT) in our CAP/CLIA accredited lab for use in patient selection.
  • Analytical validation: While delivering the biomarker solution as an LDT, Flagship and our partner will collect the analytical data to ensure that it is accurately selecting the appropriate data to understand the performance of the biomarker.
  • Clinical validation: While delivering the biomarker solution as an LDT, Flagship and our partner will collect the performance data to ensure that it is accurately selecting the appropriate patients for therapy.
  • PHASE III / FDA FILING: Drug-diagnostic registration: Flagship will work with our partners to ensure that the analytical and clinical data collected during the clinical trial shows that the performance of the LDT is sufficient to support a CDx.
  • LAUNCH: Commercial support: Flagship’s CAP/CLIA lab can support any tissue-based CDx test within the U.S. Our global partners, or any lab capable of running the validated IHC/ISH assay, can support the wet assay portion of the test while Flagship can perform image analysis on images obtained from any of these labs.


We hosted an extensive Q&A session following the webinar. To hear the questions, as well as the answers from our experts, you can view the recorded webinar.

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