Challenges for biomarkers

Regulatory challenges

The regulation of medicines is evolving, especially relating to the use of novel 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 interchangeable terms. For a biomarker to be used as a surrogate endpoint, studies will be done to assess the direct relationship of the biomarker with:

• The development of the disease.
• A treatment intervention with an important clinical endpoint.

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

• They can be measured earlier, more easily or frequently and with higher precision.
• They may be less affected by other treatments, reduce the size of samples 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 demonstrate the potential to deal with unmet medical conditions. In ‘accelerated’ procedures however, post-marketing data is required to ‘verify and describe the medicine’s clinical benefit’. Post-marketing data is also required to resolve remaining uncertainty as to the relation of the surrogate endpoint (upon which approval was based) to clinical benefit, or the observed clinical benefit to ultimate outcomes.

The main characteristic of a surrogate endpoint is that it is objectively measured and evaluated as an indicator of:

• Normal biologic processes - how things work within the body;
• Pathogenic processes - how a disease develops, or;
• 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 benefit (or harm, or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence. Just having a good ‘correlation’ does not make a good surrogate endpoint. As an example, an increase in something called ‘prostate specific antigen’ (PSA) is correlated with prostate cancer, in other words, people who have prostate cancer often also have higher levels of PSA. However, it is unreliable 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 being used in the development of medicines that are targeted to 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. Such products are given benefits when they are authorised, such as ‘market exclusivity’. This means that other companies will not be authorised to market a similar medicine or ‘generic’ for 10 years. The EMA is receiving an increasing number of requests for orphan designation for new medicines. This has resulted in the EMA building up considerable experience in assessing the potential benefits and limitations of biomarker use for regulatory purposes.

Medicines developers are being encouraged to engage with regulators at an early stage when they are considering using novel biomarkers. Developers of novel biomarkers 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.

Validating biomarkers to meet regulatory standards can be complex and expensive. This is especially challenging 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. Licensing a medicine and its companion diagnostic together adds an extra layer of complexity to the approval process.

Ethical challenges

Ethical issues that arise associated with handling of personal medical data, in biomarker research are those linked to the storage and use of tissue samples.

In addition, wider concerns have been raised about the impact of targeted medicine (which is largely based on biomarker research). For example, as targeted treatments only bring benefits to the sub-population of patients that respond to them, who will make sure that medicines are developed for those who fall outside of this sub-population?