Biomarkers in clinical trials: Drug Development

 

Introduction:

In order to develop a drug and release into market we need to perform clinical trails for estimating the safety and efficacy of the drug. Biomarkers are cellular elements or components of the body which alter in concentrations in response to a disease or disorder or with response to a drug or a therapeutic procedure. Biomarkers play a key role in each and every stage of drug development from pre-clinical phase to the completion of study. Robust and validated biomarkers are needed to improve diagnosis, monitor drug activity and therapeutic response and guide the development of safer and targeted therapies for various chronic diseases. While different types of biomarkers have been impactful in the field of drug discovery and development, the process of identifying and validating disease specific biomarkers has been quite challenging. Recent advances in multiple ‘omics’ (multi-omics) approaches (e.g., genomics, transcriptomics, proteomics, metabolomics, cytometry and imaging) in combination with bioinformatics and biostatistics have made it possible to accelerate the discovery and development of specific biomarkers for complex chronic diseases. Although many challenges still need to be addressed, current efforts for the discovery and development of disease-related biomarkers will assist in optimal decision-making throughout the course of drug development and improve our understanding of the disease processes. Furthermore, effective translation of the preclinical biomarkers into the clinic will pave the way towards effective execution of personalised therapies across complex disease areas for the benefit of patients, healthcare providers and the bio-pharmaceutical industry. In the present blog we discuss about the different types of Biomarkers and their applications in clinical trials.

Role of biomarkers in clinical trials:

Biomarkers are key indicators for pharmaceutical companies in identification and development of drugs for different indications. Currently, the role of biomarkers is evolving in the clinical research, assisting in the design of personalized treatments which are specific to each patient’s condition and genetic make-up. Biomarkers can serve as early warning systems for your health. For example, high levels of lead in the bloodstream may indicate a need to test for nervous system and cognitive disorders, especially in children. High cholesterol levels are a common biomarker for heart disease risk. Many biomarkers come from simple measurements made during a routine doctor visit, like blood pressure or body weight. Other biomarkers are based on laboratory tests of blood, urine, or tissues. Some capture changes at the molecular and cellular level by looking at genes or proteins. Biomarkers are also vital in later stages of drug development and are used in clinical research and clinical trials to assess response to treatments. Biomarker use in clinicals trials has expanded over the last few decades. Designing a protocol that incorporates biomarkers can reduce trial timelines and increase the chance of success. However, biomarkers remain underutilized for a variety of reasons. Evaluating the trends in biomarker use allows us to monitor the effectiveness of new strategies and identify areas of opportunity. In this blog we are going to explore different types of biomarkers and their role in clinical trials.

Figure 1: A multi-omics approach for the discovery and validation of biomarkers to probe multidimensional phases of Clinical trials.

Types of biomarkers in clinical trials:

Several biomarkers have been developed to assist in diagnosis and prognosis of specific diseases, disease progress and patient response to treatments, assist in identification and validation of novel targets, provide insights in drug mechanism of action, help to characterise disease sub populations, to establish treatments for the patients and predict treatment response (personalised medicine).

Biomarkers can be classified based on their area of applications such as predictor, diagnostic, prognostic, mechanistic, pharmacodynamic, safety and surrogate end point biomarkers (Table 1)

Table 1: Types of biomarkers

Biomarker category	Description	Example
Diagnostic	A biomarker used to detect or confirm presence of a disease or condition of interest or to identify individuals with a subtype of the disease	Sweat chloride may be used as a diagnostic biomarker to confirm cystic fibrosis
Monitoring	A biomarker measured serially for assessing status of a disease or medical condition or for evidence of exposure to (or effect of) a medical product or an environmental agent	Monoclonal protein (M protein) level in blood may be used as a monitoring biomarker to evaluate whether individuals diagnosed with monoclonal gammopathy of undetermined significance (MGUS) are showing signs of progressing to other disorders, including some types of blood cancer which may require treatment.
Pharmacodynamic/response	A biomarker used to show that a biological response has occurred in an individual who has been exposed to a medical product or an environmental agent	Serum LDL cholesterol may be used as a pharmacodynamic/response biomarker when evaluating patients with hypercholesterolemia, to assess response to a lipid-lowering agent or dietary changes.
Predictive	A biomarker used to identify individuals who are more likely than similar individuals without the biomarker to experience a favourable or unfavourable effect from exposure to a medical product or an environmental agent	Breast Cancer genes 1 and 2 (BRCA1/2) mutations may be used as predictive biomarkers when evaluating women with platinum-sensitive ovarian cancer, to identify patients likely to respond to poly (ADP-ribose) polymerase (PARP) inhibitors.
Prognostic	A biomarker used to identify likelihood of a clinical event, disease recurrence or progression in patients who have the disease or medical condition of interest	Breast Cancer genes 1 and 2 (BRCA1/2) mutations may be used as prognostic biomarkers when evaluating women with breast cancer, to assess the likelihood of a second breast cancer.
Safety	A biomarker measured before or after an exposure to a medical product or an environmental agent to indicate the likelihood, presence, or extent of toxicity as an adverse effect	Serum creatinine may be used as a safety biomarker when evaluating patients on drugs that affect kidney function to monitor for nephrotoxicity.
Susceptibility/risk	A biomarker that indicates the potential for developing a disease or medical condition in an individual who does not currently have clinically apparent disease or the medical condition	Apolipoprotein E (APOE) gene variations may be used as susceptibility/risk biomarkers to identify individuals with a predisposition to develop Alzheimer’s disease.

Application of biomarkers in preclinical and clinical studies:

Use of biomarkers from pre-discovery to late clinical drug development (Figure 2) and decision making is critical to evaluate activity in animal models, link animal and human pharmacology via proof-of-mechanism or other observations, evaluate safety in animal models and assess human safety early in development. Additionally, every stage of drug development has its own specific set of biomarkers that may or may not be applicable to other stages.

Examples of biomarkers in preclinical studies are serum chemistries, cell surface protein expression, drug PK/PD measurements, drug metabolising isoenzyme phenotype, serum transaminases, genomic expression profile, drug distribution or receptor occupancy via imaging.

Biomarkers in clinical studies have been used for diagnosis, a tool for staging disease, as indicators of disease status, and to predict and/or monitor clinical response to a therapeutic intervention (e.g., electrocardiogram, PET brain image, serum chemistries, auto-antigens in blood, bone densitometric measurement, pulmonary function test, neonatal Apgar score). Biomarkers used in late clinical development are psychometric testing, pain scales, imaging studies, culture status (antimicrobials), pulmonary function tests, serum chemistries and electrocardiogram. Moreover, biomarkers have the potential to reveal prognostic information about the future health status of a patient whereas diagnostics classify patients at one point in time.

Regulatory landscapes for biomarkers:

Rapid development of regulations in biomarkers field began in early 21st century and is closely linked to the development of the ‘personalised medicine’ concept involving delivery of tailored therapy to a particular patient, based on his genetic and epigenetic information. ICH E15 Guideline was published in 2006 and defines pharmacogenomics (PGx, study of variations of DNA and RNA characteristics as related to drug response) and pharmacogenetics (PGt, study of variations in DNA sequence as related to drug response). Genomic biomarkers are DNA or RNA characteristics that are a crucial part of drug development and essential for successful regulatory approval. Examples of the use of genomic biomarkers in drug development include:

understanding of the mechanistic basis for lack of efficacy, occurrence of adverse drug reactions or drug-drug interactions, clarifying differences in response in clinical trials as well as differences in pharmacokinetic (PK) and pharmacodynamic (PD) parameters and enrichment and stratification in clinical trials to facilitate accelerated development. 

Numerous PGx and PGt related guidelines are available from both EMA and FDA.

Conclusion:

A better coordinated experimental and clinical design, more standardised multi-omics and multi-parametric technology and analysis platforms, as well as a collaborative effort between scientists, clinicians, biopharmaceutical industry and regulatory authorities should expedite the discovery of validated and qualified biomarkers to a much greater extent. Which in turn leads to better development in accessing safety and efficacy in drug development.

References:

1. Seyhan, A. A. (2010). Biomarkers in drug discovery and development. Eur Biopharm Rev, 5, 19-25.

2. Gromova, M., Vaggelas, A., Dallmann, G., & Seimetz, D. (2020). Biomarkers: opportunities and challenges for drug development in the current regulatory landscape. Biomarker Insights, 15, 1177271920974652.

3. Antoniou, M., Kolamunnage-Dona, R., Wason, J., Bathia, R., Billingham, C., Bliss, J. M., ... & Jorgensen, A. L. (2019). Biomarker-guided trials: challenges in practice. Contemporary Clinical Trials Communications, 16, 100493.

4. Buyse, M., Michiels, S., Sargent, D. J., Grothey, A., Matheson, A., & De Gramont, A. (2011). Integrating biomarkers in clinical trials. Expert review of molecular diagnostics, 11(2), 171-182.

5. Schuck, R. N., Delfino, J. G., Leptak, C., & Wagner, J. A. (2022). Biomarkers in drug development. In Atkinson's Principles of Clinical Pharmacology (pp. 323-342). Academic Press.

6. Gosho, M., Nagashima, K., & Sato, Y. (2012). Study designs and statistical analyses for biomarker research. Sensors, 12(7), 8966-8986.

Student Name: Manju Lakshmi Seelam

Student ID: 132/0720231

Qualification: M. Pharmacy

e-Mail ID: manjulakshmi977@gmail.com