The average cost of drug development is $1 Billion over the course of 10 years. In recent times, there has been a need for personalized medicine treatments. In many therapeutic areas, patient therapy can be ineffective, oncology and Alzheimer drugs, in particular, are the two most ineffective. Personalized medicine would enable the ability to take advantage of the fact that many tumors are driven by certain genetic mutations.

Biomarkers are important for the success of clinical trials, and for that reason, it's beneficial to adopt the 5R framework: Right target, Right tissue, Right safety, Right patients, Right commercial potential, and Right culture. Take for instance the Crizotinib (Pfizer ALK inhibitor) Approval Success Story: Two single arm studies (n=119 and n=136) in four years with shorter time, fewer patients, and less money.

Over the course of this article, clinical biomarker considerations will be discussed including objectives, regulations, guiding principles, the four stages of a clinical biomarker study, and essential job roles and challenges. Additionally, biomarker considerations for immuno-oncology studies will also be highlighted.

Clinical Biomarker considerations in general

The main objectives of clinical biomarkers are to:

  1. Demonstrate clinical Proof of Mechanism/Proof of Principle (e.g. Does the drug hit the target? Can one assess drug effect?)
  2. Guide clinical dose selection based on optimal biological activity
  3. Evaluate potential patient stratification markers

What’s interesting to note is that drug resistance biomarkers, safety biomarkers, and efficacy biomarkers are less common in early phase clinical trials. Therefore, it is important to align the biomarker strategy with biomarker objectives as there are not many regulations for biomarkers in clinical trials.

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GCP needs to be followed for biobanking/sample collection, including validated controlled temperature units as well as 21 CFR Part 11 compliant sample management systems for complete chain of custody. What’s more, a CLIA/Validated assay is required for patient decision-making.

For exploratory biomarkers, generally fit for purpose validation is performed. As for lab quality practices (as determined internally), it is advised that all the documentation and the proper quality controls are in place.

Guiding Principles for Biomarkers in Clinical Trials:

  1. If there are no samples, there won’t be any translational research.With samples, however, there is a possibility
  2. Robust scientific justification and assay clinical feasibility evaluation is needed for the sample and biomarker research proposed
  3. Ensure quality samples are collected properly. It’s beneficial if the samples can be used for exploratory biomarker research as well aspotentially for CDx development in the future

In a biomarker clinical trial, it's essential that the study protocol and the informed consent form are clearly defined. This is  to ensure quality collection, broad consent, and maximum use of the data.

There are a number of pre-analytical issues that need to be considered to ensure samples can be used for the assay needed. This is challenging considering there are constant emerging technologies. However, broad consent can enable future and exploratory use. ICF tracking and reconciliation for sample permission (including storage, disease, drug study, CDx development, return of data) need to be performed. For data mining, it's important the data are integrated with samples. Sample availability information and proper sample governance is required for effective use of samples collected in clinical trial.

The Four Stages of Clinical Biomarker Study

Clinical Biomarker Stage 1: Prepare for Clinical Biomarker Plan

Timing: After candidate selection, one year before clinical introduction


  1. Propose biomarker samples to be collected in phase I trial
  2. Propose a set of potential pharmacodynamics and patient stratification  biomarker studies to be tested in samples collected in phase I clinical trial
  3. Provide scientific rationale/evidence for samples collected and studies proposed

Team members: Discovery, Biomarker Research, IPTL, Clinical

Clinical Biomarker Stage 2: Implement Clinical Biomarker Plan

Timing: Before clinical introduction


  1. Ensure clinical team buy-in on the biomarker strategy, addressing on-going questions from clinical team
  2. Right biomarker languages in clinical study protocol
  3. Right biomarker languages in Informed Consent Form
  4. Proper instruction in Lab Manual

Team member: Study manager, study director, clinical lead, IPTL

Clinical Biomarker Stage 3: Monitoring Clinical Biomarker Assay/Samples

Timing: During clinical trials


  1. Modify biomarker strategy as needed, addressing ongoing questions from the clinical team
  2. Work with CRO or researchers to ensure that quality results can be obtained
  3. Addressing sample collection issues with sites and the study manager, i.e. sample reconciliation
  4. Develop data transfer specifications with the data management team

Team members: CRO, clinical team (study manager, study director, data management)

Clinical Biomarker Stage 4: Conduct and Report of Clinical Biomarker Data Analysis

Timing: After clinical trials


  1. ICF reconciliation
  2. Perform additional exploratory biomarker assays
  3. Clinical biomarker assay report
  4. Clinical biomarker analysis and report
  5. Transfer data to clinical database if needed

Team member: Biobank, Researcher, bioinformatician, biostat, data management

Essential job roles in the Clinical Biomarker area

Roles: Biomarker Lead


Developing Biomarker Strategy: Work with Discovery, Biomarker research, IPTL, Clinical to provide scientific rationale/evidence for biomarker samples collected and studies proposed in clinical trials


  • Ph.D. with in-depth knowledge of preclinical program and some clinical biomarker knowledge
  • Great project/alliance management skills to gain consensus and ensure development of feasible clinical biomarker plan in a timely manner
  • One person can server Biomarker Lead for no more than two projects due to work load
Roles: Biomarker Operation


Implementing Biomarker Plan:

  • Working with Biomarker Lead, study manager, study director, clinical lead, IPTL to put right biomarker languages in clinical study protocol, right biomarker languages in Informed Consent Form and proper instruction in Lab Manual
  • Standardizations and streamlined processes across programs and efficient operation
  • Addressing sample collection issues with sites and study manager and sample reconciliation


  • B.S. and M.S. experiences with both clinical operation and clinical biomarker research
  • Detail oriented and organized
  • Clear understanding of biomarker plan
  • Stay focused to implement the clinical biomarker plan (not own agenda)
  • One person can cover a business group or more through strategic partnership with vendors
Roles: Biomarker Outsourcing


  • Technical evaluation of clinical biomarker vendors
  • Work with CRO or researcher to ensure that quality results can be obtained


  • Ph.D. with in-depth biological knowledge
  • Good PM and communication skills
  • Clear understanding of biomarker plan
  • Stay focused to implement the clinical biomarker plan (not own agenda)
  • One person can cover a business group or more through strategic partnership with vendors

Challenges in the Clinical Biomarker Area

For biomarker-driven trials, there are a number of challenges that need to be factored into the equation. For a start, they require a multi-disciplinary team, which can at times make it difficult to achieve alignment among all involved. Additionally, start-up timelines are typically short, and once trials are underway, the clinical biomarker results are invariably complex and difficult to interpret. This places an increased emphasis on biomarker results for RP2D (Recommended Phase II Dose) as well as the combination strategy.

Developing a Clinical Biomarker Strategy in Immuno-Oncology

For a clinical trial studying the general immune system, there are three factors that need to be considered:

  • Immune effector mechanism (MHC)
  • General immune status (lymphocyte count)
  • Gut microbiome

For a trial with a tumor-immune interaction, four considerations must be factored:

  • Tumor foreignness (mutational load, MSI Status)
  • Immune infiltration status (e.g. Intratumoral CD8)
  • Tumor metabolism effect on immune system (LDH, glucose use)
  • Local inhibitory factor (soluble factors, PD-L1)

There has been increased interest in identifying biomarkers to guide patient selection and drug safety. Biomarkers for response and resistance of drugs differ based on different mechanisms of action of the pathway targeted by the drug. In the classic paradigm for genetic biomarker-driven therapies (BRAF, EGFR and ALK), the drug is absolutely dependent on the presence of a specific mutation that can be detected by a DNA-based test. The biomarker strategy for targeted kinase inhibitor may not apply to immunotherapies that target molecules broadly expressed across a dynamic range. Immune checkpoint inhibitors have a broad range of activity in a number of cancer types but other cancer types are more resistant to these therapies. This underscores the need for more biomarker development.

Biomarkers are needed to guide patient selection for monotherapy, combination therapy and treatment sequence. For the same drug, different biomarkers might be required for different tumor types. Furthermore, many preliminary biomarkers are found to be not sufficiently robust to be used clinically. Therefore, broad immune profiling and multifactorial biomarker approaches are needed for the discovery of biomarkers in immunotherapy. Combination trials ­– even early exploratory ones – should be biomarker rich in order to derive the most information as efficiently as possible. Intensive pharmacodynamics and correlative immune studies is the only way that biomarker candidates can be identified.