Definition of biomarkers and efficacy end-points

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Course: Early Clinical Development
Book: Definition of biomarkers and efficacy end-points
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Date: Monday, 27 June 2022, 9:43 AM

1. Introduction

Biomarkers are indicators that measure normal processes or disease processes in the body. This might include an individual’s response to a medicine.

For example body temperature is measured to indicate a fever. The concept of biomarkers is not new. Some examples of biomarkers are:

  • Biological substances (‘biochemicals’), such as enzymes or hormones - these may be found in the blood or in tissue samples (biopsies).
  • Gene changes.
  • Images from Magnetic Resonance Imaging (MRI).

Biomarkers can be any measurements that can reliably be made and that can tell us something about a person’s health or disease state. This might include the persons’ response to a therapy. It has to be considered that levels of specificity and sensitivity of a given marker may vary widely.

In other words, the accuracy of biomarkers varies and therefore not all markers are suitable for drug development. Even more challenging is the use of biomarkers for regulatory purposes (see below).

The main focus of this topic is molecular biomarkers in medicines development. There is a special emphasis on recent genomic technologies, i.e. those that look at genes.

1.1. Aims of biomarker use

Biomarkers can be used to measure:

  • Normal biological (physiological) processes in the body.
  • Pathological (disease) processes in the body.
  • A person’s response to a treatment or a medicine.

The two main goals of biomarkers in medicines development are:

  • To streamline medicines development. In a clinical study, researchers want to directly measure the patient’s response to a treatment. But when this is not directly possible, biomarkers may offer another way to measure an outcome (a so-called surrogate endpoint). Biomarkers can also help select which patients are most suited to take part in a clinical study.
  • To tailor treatment to individual patients. Biomarkers help researchers improve how to predict a person’s risk of disease, how a disease might progress once it is diagnosed, and how an individual will respond to a medicine. Also, healthcare professionals are beginning to use biomarkers to make decisions on safer and more effective treatment. (1)

There are many established biomarkers that are known to have clinical use. That is, they are proven to give reliable measures of underlying biological processes. Therefore, their use in medicines development is well accepted. For example, a clinical endpoint in a clinical trial (such as relief of symptoms, survival, or disappearance of a tumour) can in some cases be replaced with an established biomarker. This is known as a surrogate endpoint. For the medicine to receive a marketing authorisation, there must be good evidence that the biomarker used is a valid substitute for the clinical endpoint.

Examples of established biomarkers:

  • Glucose levels in a patient’s blood (blood sugar level) can be used to monitor if an individual patient is responding to diabetes treatment. Uncontrolled glucose levels are one of the major problems in diabetes patients who are not treated properly. 
  • Magnetic resonance imaging (MRI) of a patient’s brain can help assess disease status in multiple sclerosis. This might be monitored instead of clinical disease progression, or the patient experiencing relapses.

In addition, many new exploratory biomarkers are being discovered and used during the development of new medicines. Many of these use so-called ‘omics’ technologies: genomics, proteomics and metabolomics:

  • Genomics is a branch of genetics. It applies various methods to sequence, assemble, and analyse the function and structure of genomes.
  • Proteomics is the large-scale study of proteins, particularly their structures and functions and quantity. Proteins are vital parts of living organisms, as they are the main components of the metabolic pathways of cells.
  • Metabolomics is the scientific study of chemical processes that involve ‘metabolites’. Metabolites are small molecules which are left behind after a chemical process has taken place in a cell. In other words, they are the ‘product’ of the process.
  • Pharmacogenetics or pharmacogenomics specifically use genetic or genomic information (i.e. genetic or genomic biomarkers) in the development and use of medicines.

(1) Industry Pharmacogenomics Working Group (I-PWG). Understanding the Intent, Scope, and Public Health Benefits of Exploratory Biomarker Research.  A Guide for IRBs/IECs and Investigational Site Staff.

1.2. Biomarkers in the Pharmaceutical Industry Today

Nearly a third of the medicines in development today have some form of a genomic or proteomic marker. There has been a rapid increase over recent years.(1)

This varies across disease areas, however cancer (oncology) research was one of the first areas where the use of such biomarkers was adopted.

  • Biomarkers are being used to make exploratory trials of medicines more efficient. Exploratory trials are early trials/Phase I trials.
  • Only a limited number of biomarkers can be used as a substitute for a clinical endpoint in a confirmatory trial. Confirmatory trials include late stage trials/Phase III. Biomarkers may however be used in late stage trials in combination with clinical endpoints.
  • For medicines that are being designed for specific molecular targets, only a sub-group of patients might respond. It is important to identify these patients for clinical trials, using biomarker measures.

(1) Evers M, Kulkarni S, Ma P, Moller M, Ostojic I. Managing for success in biomarker R&D: Challenges and opportunities. In Personalized Medicine The Path Forward. McKinsey and Company (2013).

1.3. Companion Diagnostics

A validated (proven) test for each biomarker is needed.The test will accurately measure whether a biomarker is present and at what level. It may be a laboratory test or a test kit. The test may help to:

  • Select patients who are likely to respond to a medicine.
  • Exclude patients who are likely to have an adverse reaction.
  • Determine the best dose for a patient.

‘Companion diagnostics’ are tests that are validated and approved for marketing in combination with a new medicine. They can be:

  • Developed once a medicine is on the market.
  • Developed alongside a medicine that is still under development.

Many companies that develop therapies for cancer have also begun to consider how a diagnostic test can benefit the treatment. The trend is to develop medicines and companion diagnostics together, rather than have both developments happen in isolation. Some examples: Sight: Companion diagnostics (CDx): definition, importance and role (sightdx.com) or Foundation Medicine: Companion Diagnostics Explained: Their Critical Role in Cancer Care and Our Latest Approvals | Foundation Medicine

More information:

1) EMA: The In-Vitro Diagnostic Devices Regulation (Regulation (EU) 2017/746) introduces a new classification system for companion diagnostics and the obligation to undergo a conformity assessment by a notified body.

2) Biomarker and Companion Diagnostics—A Review of Medicinal Products Approved by the European Medicines Agency
https://www.frontiersin.org/articles/10.3389/fmed.2021.753187/full

3) Questions & Answers-practical arrangements on the companion diagnostics consultation procedure to the European Medicines Agency by notified bodies
https://www.ema.europa.eu/en/documents/other/questions-answers-practical-arrangements-companion-diagnostics-consultation-procedure-european_en.pdf

2. How Biomarkers Are Used In Medicines Development

Many drug candidates fail at each development phase and will not be taken further (also known as ‘attrition’). But biomarkers have the potential to increase the efficiency of medicines development, by:

  • Speeding up clinical trials: they can be used to detect an effect (or lack of effect) earlier and more frequently than if only a clinical endpoint is used. For example:
    • A panel of biomarkers has been used in the early phases of a clinical trial for a psoriasis treatment. The biomarkers included ‘epidermal thickness’ (i.e. thickness of the outer layer of skin) and the activity (expression) levels of several genes. These were both measured in skin biopsies. (1)
    • Haemoglobin levels have been used in phase III trials to support development of therapies for ‘type 1 Gaucher disease’. This is a rare disease that affects multiple organ systems and shortens life expectancy, but it can take years to progress. (2)

  • Streamlining clinical trials: they can help prediction (forecast), early detection and monitoring adverse reactions.
    • One of the most common serious side effects of medicines is damage to the liver. Biomarkers that give an early indication of liver health have long been used during medicines development, and new ones are still being discovered. (3)
    • The importance of safety biomarkers was highlighted in 2011, when new guidelines were proposed for their validation. (4)

  • Improving clinical trials through better patient selection: this reduces ‘heterogeneity’ (diversity) and is the most common goal for genomic biomarkers in medicines development. (5) Genomic biomarker(s) can be used to:
    • Identify patients with a particular disease sub-type or severity – for example,  most but not all patients with ‘chronic myeloid leukaemia’ have the ‘Philadelphia’ chromosome which is a particular genetic abnormality.
    • Exclude patients at increased risk of serious adverse reactions – for example, melanoma patients are at risk of getting worse if treated with kinase inhibitors and their tumours do not have a certain mutation in the ‘BRAF’ gene.
    • Identify patients with a high chance of benefitting from a particular medicine - for example, kinase inhibitors and patients with BRAF-mutated melanomas. In the same way, genomic biomarkers can help avoid that patients are exposed to a new drug if they are unlikely to benefit.

  • Improving our understanding of the way new medicines work, and leading to new approaches to medicines development in both non-clinical and clinical phases.
  • Showing an added ethical benefit.
  • A trial can be stopped sooner if no benefit is to be gained by the patients in the trial.
  • A medicine with a positive effect might be authorised sooner and hence be prescribed earlier for patients who will benefit.
References

(1) Papp et al. Anti-IL-17 Receptor Antibody AMG827 Leads to Rapid Clinical Response in Subjects with Moderate to Severe Psoriasis: Results from a Phase I, Randomized, Placebo-Controlled Trial. J Inv Derm 2012 132, 2466–2469.

(2) Bai JPF, Barrett JS, Burckart GJ, Meibohm B, Sachs HC, Yao L. Strategic biomarkers for drug development in treating rare diseases and diseases in neonates and infants. The AAPS Journal, 2013; 15(2):447-454.

(3) Schomaker S, Warner R, Bock J, Johnson K, Potter D, Van Winkle J, Aubrecht J. Assessment of emerging biomarkers of liver injury in human subjects. Toxicological Sciences 2013 132(2):276-83.

(4) Matheis K et al. A generic operational strategy to qualify translational safety biomarkers. Drug Discovery Today 2011: 16; 600-608.

(5) EMA: Good pharmacogenomic practice: Current effective versionhttps://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacogenomic-practice-first-version_en.pdf  - This document describes requirements related to the choice of appropriate genomic methodologies during the development and the life-cycle of a drug. It discusses the principles for a robust clinical genomic dataset. It also highlights the key scientific and technological aspects for the determination and interpretation of the genomic biomarker data and their translation into clinical practice.

3. Challenges for Biomarkers in Medicines Development

Companies face new technical and regulatory challenges as biomarkers are used more in pharmaceutical research. The field as a whole also faces several ethical challenges. These are summarised below.

3.1. Technical Challenges

  • Biomarkers used in clinical trials must be validated (‘qualified’): is there scientific evidencethat the biomarker test is accurate, reliable, sensitive and specific enough? Companies will have to collect all this data for each biomarker they develop.

  • Biomarkers must be valid measures: For example, if a biomarker is used to predict how severe a disease may get, is there enough evidence of this ‘predictive ability’? In other words, has it been shown to predict severity enough times before?

  • Sample collection and processing methods must be consistent (e.g. for biopsies or blood samples). Variations in the way samples are handled can affect the results of biomarker tests. This could make the results of a trial invalid.

  • The IT systems used for data management and data analysis must be robust and fast to cope with the amount of data generated. All biomarker measurements must be correctly linked with individual patients.
  • When a companion diagnostic is needed to prescribe a new medicine , a new ‘platform’ or kit for testing patients in the clinic may need to be developed. The test kit will usually need to be ready for use during the large confirmatory trials of the medicine (Phase III). It is not ready until it has been validated and the validation results show that the diagnostic is accurate and clinically useful.

3.2. Regulatory Challenges

The regulation of medicines is evolving when it comes to new methods such as biomarkers.

A good definition of biomarker for clinical trial purposes is the following one, already formulated by Temple, in 1999: “A biomarker is a laboratory or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint. The endpoint is a direct measure of how a patient feels, functions, or survives and that is expected to predict the effect of the therapy.”

However, in the regulatory field, biomarkers and surrogate endpoints are not synonymous. For a biomarker to be used as a surrogate endpoint, studies will be done to assess the direct relationship of the biomarker with:

There are advantages of using validated biomarkers as surrogate endpoints, for example:

  • They can be measured earlier, more easily or frequently and with higher precision than clinical endpoints.
  • They may be less affected by other treatments
  • They may reduce the size of the sample required and allow researchers to make faster decisions.
  • There are important ethical advantages in diseases with poor prognosis.

This is the reason why surrogate endpoints (if validated) are often used in ‘fast-track’ or ‘accelerated’ approval procedures. They will assist the development and speed up the review of new medicines that are intended to treat serious or life-threatening conditions. And/or they can demonstrate the potential to deal with unmet medical needs. In ‘accelerated’ procedures however, data must ‘verify and describe the medicine’s clinical benefit’ after it has been marketed. Post-marketing data are also required to resolve remaining uncertainty on the relation of the clinical benefit to the surrogate endpoint (upon which approval was based). Or the relation of the observed clinical benefit to ultimate outcomes.

What characterises a surrogate endpoint is that it is objectively measured and that it is evaluated as an indicator of:

  • Normal biologic (physiological) processes - how things work within the body.
  • Pathogenic processes - how a disease develops.
  • Pharmacological responses to a therapeutic intervention - how the body responds to the use of a medicine or other therapy.

It should be directly related to clinical outcomes.

For regulatory purposes, surrogate endpoints represent only a ‘sub-set’ of biomarkers. A biomarker can be called a surrogate endpoint if it is expected to predict clinical outcomes. This could be harm, or lack of benefit based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence. Just having a good ‘correlation’ or match does not itself make a good surrogate endpoint. An example is the increase in something called ‘prostate specific antigen’ (PSA). PSA is correlated with prostate cancer, in other words, people who have prostate cancer often also have higher levels of PSA. However, it cannot be relied on as a surrogate endpoint. This is because levels of PSA may be reduced when the patient is treated for prostate cancer, but there is no effect on the long term outcome of the disease.

A strong example is in the development of antiretroviral medicines for HIV and AIDS. Levels of ‘CD4 lymphocytes’ and changes in ‘HIV-RNA’ plasma levels can now be used as surrogate endpoints. Previously, studies would have been based on hard clinical endpoints such as progression of the HIV infection to AIDS and/or patient survival.

Biomarkers are also used for medicines that are developed for a specific sub-population of patients. A medicine that is only going to be prescribed to a small sub-population of patients can be labelled by the European Medicines Agency (EMA) as an ‘orphan’ medicine. Companies that develop such products are given benefits when the medicinal products are authorised, such as ‘market exclusivity’. This means that other companies will not be allowed to market a similar medicine or ‘generic’ for 10 years (market exclusivity). The EMA receives an increasing number of requests for orphan designation for new medicines. This has given the EMA considerable experience in how to assess the possible benefits and limitations of biomarkers used for regulatory purposes.(1)

Medicines developers are encouraged to engage with regulators at an early stage when they consider using new biomarkers. They can submit their plans to use the biomarkers to the EMA. They can present the scientific evidence they have collected to validate specific biomarkers, so that the EMA’s Committee for Medicinal Products for Human Use (CHMP) can give an opinion on their use.

It can be complex and expensive to validate biomarkers so that they can meet regulatory standards. This is especially the case if a biomarker is to be used as a surrogate endpoint. In this case, a dedicated clinical trial is required that is designed to test the link between the biomarker and the clinical endpoint.

Finally, in the EU, medicines and diagnostics are regulated differently. Obtaining a marketing authorisation for a medicine and its companion diagnostic together adds an extra layer of complexity to the approval process.

(1) Tsigkos S, Llinares J, Mariz S, Aarum S, Fregonese L, Dembowska-Baginska B et al. Use of biomarkers in the context of orphan medicines designation in the European Union. Orphanet Journal of Rare Diseases, 2014; 9:13.

3.3. Ethical Challenges

Many ethical issues are seen in biomarker research. These issues often have to do with the storage and use of tissue samples, and how associated personal medical data are handled.

In addition, wider concerns have been raised about the impact of targeted medicine which is largely based on biomarker research. One concern is that targeted treatments only benefit the sub-population of patients that respond to them. Who will then make sure that medicines are developed for those who fall outside of this sub-population?

4. 'Take-home' messages

  • Companion Diagnostics are tests that are validated and approved for marketing in combination with a new medicine. Since in the EU, medicines and diagnostics are regulated differently, obtaining a marketing authorisation for a medicine and its companion diagnostic together adds an extra layer of complexity to the approval process.

5. Further Reading (optional)

If you like to learn more about this topic, we recommend having a look at the following resources:

  • Bai JPF, Barrett JS, Burckart GJ, Meibohm B, Sachs HC, Yao L. Strategic biomarkers for drug development in treating rare diseases and diseases in neonates and infants. The AAPS Journal, 2013; 15(2):447-454.
  • Tsigkos S, Llinares J, Mariz S, Aarum S, Fregonese L, Dembowska-Baginska B et al. Use of biomarkers in the context of orphan medicines designation in the European Union. Orphanet Journal of Rare Diseases, 2014; 9:13. (open access article)
  • Evers M, Kulkarni S, Ma P, Moller M, Ostojic I. Managing for success in biomarker R&D: Challenges and opportunities. In Personalized Medicine The Path Forward. McKinsey and Company. 2013.
  • Industry Pharmacogenomics Working Group (I-PWG). Understanding the Intent, Scope, and Public Health Benefits of Exploratory Biomarker Research.  A Guide for IRBs/IECs and Investigational Site Staff.
  • Papp et al. Anti-IL-17 Receptor Antibody AMG827 Leads to Rapid Clinical Response in Subjects with Moderate to Severe Psoriasis: Results from a Phase I, Randomized, Placebo-Controlled Trial. J Inv Derm 2012 132, 2466–2469.
  • Schomaker S, Warner R, Bock J, Johnson K, Potter D, Van Winkle J, Aubrecht J. Assessment of emerging biomarkers of liver injury in human subjects. Toxicological Sciences 2013 132(2):276-83.