Establishing the Standards in Biomarkers Research

Biomarkers look likely to become one of the major drivers in pharmaceutical research and drug development. They have the potential to encourage innovation, improve efficiency, save costs, and gain research organizations an advantage over their competitors.

Increasingly, many decision-makers throughout the development pipeline are turning to biomarker evidence to support their stage gate judgments. This enables patients to benefit from drugs that are more efficacious and have fewer side effects.

However, research organizations currently face a number of hurdles in realizing and passing on these benefits. Regulatory agencies are reluctant to accept biomarker-based evidence to support a drug approval without reliable standards of biomarker documentation.

The information provided by a biomarker must be trustworthy if it is to be used to support a key decision. And biomarkers must become established enough that they shift the research paradigm away from the 'blockbuster' model to a smaller market - but with more carefully targeted products.

It is believed that every disease process may have a number of biomarkers associated with it, though the presence of a biomarker by itself may not be useful in clinical practice. To be worthwhile, the biomarker must be a signaling characteristic (ie, a characteristic with a known correlation between the evidential quantity and the disease state) that can be measured accurately, easily and cheaply, preferably using noninvasive techniques such as medical imaging, blood or urine analysis, or gene chips.

Many scientists already use a core set of these biomarkers, but this is insignificant compared to the thousands of biomarkers that may exist and are yet to be discovered, documented or quantified. Even excluding those that are less reliable, or less easy to measure, this suggests a wealth of indicative information that can be employed in every phase of drug discovery, development and clinical practice.

As biomarker research gathers pace, an understanding of the role of these signalers is increasing in therapy areas such as cancer, cardiology, neurology, metabolic, autoimmune and infl ammatory diseases.

Biomarkers can provide their discoverers with tangible benefits in terms of speeding up and focusing the development of associated treatments for the disease they indicate. However, most research is proprietary, and biomarkers are themselves commodities just like the drugs they help to bring to market.

Biomarker research, too, follows a similar pipeline to drug research: from discovery, through initial documentation and exploratory use in pre-clinical and clinical development. This is then followed by publication and regulatory approval, and ideally onward into widespread adoption in clinics.

Meeting Objectives
There appears to be as high an attrition rate in biomarker development similar to drug development. The end-point for a biomarker researcher may not simply be to support drug development, but to establish and manufacture diagnosis kits and software, along with licensing opportunities.

Of this research pipeline, the key stage is, naturally, regulatory approval. Without the approval of diagnosis equipment by the authorities, a biomarker remains 'nonvalidated', meaning that it is unusable for clinical practice or to support the claims made during drug development. Even if this is the case, the non-validated biomarker may still be useful in the early proof-of-concept stages of drug discovery and research.

Similarly, even with biomarkers that regulatory authorities are not confi dent enough to validate, these may still be used in laboratory, biochemical, molecular or physiological tests.

A single biomarker may have different uses, where only some of which are validated. The Her2 biomarker is an established indicator of breast cancer, and is validated for cardiovascular toxicity in patients taking certain drugs. It has however not yet been authorized for ovarian and prostate cancer.

Until now, the association between an intermediary and a disease state seems to be largely retrospective. The role of the intermediary as a reliable indicator is known first, before it becomes established as a biomarker. For example, cholesterol levels are a method of measuring risk for heart disease, blood pressure for stroke or renal failure.

The role of an authoritative biomarker database is to establish standards that can reverse this process: To wrap a wealth of objective evidence that is supported by published literature, around new biomarkers. This is to help the latter achieve validation.

------------------------------------------------------------

Benefiting from Biomarkers

Bristol-Myers Squibb's use of biomarkers provides an example of three key ways in which biomarkers can benefit pharmaceutical R&D:

1) To differentiate a phase III compound from its generic competition In a selected patient population from a phase II trial involving 161 patients, the response rate to ixabepilone rose from 18 per cent to 45 per cent. This is in comparison with a generic taxane, based on markers of sensitivity identified in studies of 18 different breast cancer cell lines.

2) Line extension of a late-stage drug Dasatinib has been launched in the US and EU for chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), and is in early-stage development for solid tumors. A strong correlation has been observed between solid tumor Src activation profile and patient response to Dasatinib.

3) To improve the risk-to-benefit ratio of an existing therapy Markers to predict incidence of lipodystrophy induced by highly active antiretroviral therapy (HAART) include an alteration in the resistin gene (coding for an adipocytederived hormone linked to obesity and diabetes), which has been associated with high risk of lipodystrophy.

------------------------------------------------------------

Catch-22
Given their potential benefits throughout the drug development process, biomarkers are still not being adopted universally.

The catch-22 is that while biomarkers remain undervalued by innovators, they will also be undervalued by regulatory authorities. By the same token, while regulatory authorities lack confidence in biomarker evidence, innovators will be reluctant to rely on them to support their stage gate decisions.

Naturally, there are some diseases where biomarker research is seen as less important than others. But even among these, future developments may lead to unexpected and beneficial innovations.

For example, if a researcher is working on defi ning the genetic basis of hypertension, the genomic aspects of that disease will be critical. This is especially true if a biomarker that indicates which patients are likely to respond to which types of therapy, can be found.

The availability of trusted, validated biomarker information may pave a way out of the catch-22 situation, by providing opportunities:

• Biomarkers can be used to detect the predisposition for disease in a population, screen for its presence and confirm its diagnosis. They can also assess its severity, predict its response to available therapies, and measure its clinical course.
• Biomarkers can be used as targets to discover new drugs. They provide improved systems for screening a library of compounds for promising candidates and decreasing the number of false results.
• The existence of viable biomarkers can be a decisive factor in determining whether or not to continue research on an entity, particularly at the proof-of-principle and proof-of-mechanism stage gates.
• Biomarkers can indicate early in the development phase, whether an entity could lead to side effects that should terminate further research. This can help reduce the attrition rate further down the pipeline and minimize risks. It is estimated that as many as 1.5 million patients are hospitalized each year due to the adverse effects of prescription drugs.
• When it comes to clinical trials, biomarkers can help to make efficacious decisions that save time and money, for example by identifying suitable subjects for initial human testing. They can also provide data sooner, with objective reliability. For example, an anticancer drug could be tested against tumor growth or progression-free period, rather than mortality.
• Biomarkers can reduce treatment overheads by optimizing dosage and measuring a patient's response more quickly and accurately. This in turn may introduce the need to measure additional biomarkers, more closely targeting the therapy to the individual patient.

These are tangible rewards for both innovator and patient, as well as a third beneficiary: the payer. As the analysis suggests, if the majority of prescription drugs only work in less than half of the patients who receive them, clinicians are wasting health authority or employer insurance scheme monies on ineffectual treatments. This could easily amount to several hundred billion dollars each year.

Meanwhile, cost pressure on those same payers means regulatory bodies will only approve drugs that are shown to be more effective than the established treatments. It is the regulatory bodies that ultimately need to be convinced by biomarkers.

Seeking Approval
During the early stages of drug discovery and development, a pharmaceutical organization can use whatever biomarkers it feels are most reliable. This is regardless of whether or not they have been validated by regulatory agencies. This is also true, to a lesser extent, during phase I and II clinical trials, so long as the biomarkers are ethically acceptable.

Later, when the candidate approaches phase III trials, the organization has no choice but to switch to those biomarkers that will be accepted by regulatory agencies as evidence for approval.

In other words, if a regulatory agency accepts one biomarker as valid for establishing efficacy, but does not accept another, it is in reality supporting research in some biomarkers but not in others.

The suspicion is that, whatever their intentions, the regulatory agencies may be exacerbating the paradox of biomarker research. Since very few of the biomarkers that have the potential to be used as indicators of efficacy or toxicology in trials have yet been validated to the standards of the Food and Drug Administration (FDA) and other agencies, the confusion threatens to stifle research altogether.

Nevertheless, the stated position of the FDA is to encourage and support biomarker research, suggesting that the appropriate inclusion of biomarker evidence is likely to speed up approval.

In its Critical Path Opportunities Report, March 2006, the FDA endorsed the importance of biomarkers. It declared taking the lead in trying to establish a regulatory framework that could expedite incorporation of biomarkers into the development process. However, it also noted that "much development work and standardization of the biological, statistical, and bioinformatics methods must occur before these techniques can be easily and widely used."

By claiming that biomarker research had "stalled", the FDA was actually highlighting its own barrier to regulatory acceptance of biomarker evidence. The authority rarely has an issue accepting biomarker data as evidence of a secondary clinical endpoint, but accepting them as evidence of a primary endpoint is a quite different matter.

If the state of the art is to assess efficacy by looking at a biochemical or physiological or molecular endpoint, the FDA generally rejects it as a satisfactory clinical endpoint for approving the drug to market. It tells the innovator that the primary endpoint must be clinically relevant to the disease and the patient's well-being.

Seizing the Initiative
The FDA does recognize that biomarkers are an area of importance to pharmaceutical innovation and personalized medicine, and is making efforts to build a framework for regulatory acceptance. Other agencies, including the European Medicines Agency (EMEA), are engaged in the same issue.

In Japan, the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health, Labor and Welfare have proposed biomarker development as a national project, and are actively promoting biomarker research.

For example, they have announced a program to investigate Beta-42 Amiloid approaches to Alzheimer's disease, and are seeking a compound related to salivary amylase and peroxidation in fat as a biomarker for stress. Recent history shows that biomarker research can be accelerated to swift approval where the need arises. With minds sharpened by the AIDS pandemic, it took only a few years of intensive searching for a biomarker to combat HIV, to accept CD4 cell counts as a validated primary endpoint.

Once a biomarker approaches or achieves validation, there is no lack of interest from pharmaceutical researchers to further develop and employ it, particularly if the biomarker may be able to gain more rapid acceptance of the marketing applications of their own candidate drugs. Physicians will also want to use biomarker diagnosis as soon as practicable, particularly if that diagnosis is simple (eg, a lab test of blood or urine samples) for a relatively common disease.

The biomarker PSA, used to assess prostate function, is an example of one such diagnosis that moved rapidly from introduction to widespread adoption in the clinics.

The fast-track biomarkers however, are exceptions. If gaining biomarker acceptance is perceived to be an uphill battle, taking years and millions of dollars, and faced with the challenges of getting approval from regulatory agencies, researchers are likely to tire of the effort. The trend may then be to shift focus elsewhere.

Meanwhile, no single innovator is likely to step forward to take the entire weight on its shoulder, as this is a fiercely competitive commercial industry where each organization works independently of its rivals. Many companies state that they have no intention of coordinating their efforts with others. The academic field is not likely to take the lead either.

It therefore falls to an objective outside body to seize the initiative.

Evolving Information Into Knowledge
There is no lack of biomarker information already in the public domain, and more is being released on a daily basis. But little of this has the level of trust and authority necessary to provide the evidential framework needed for biomarker validation by the regulatory agencies. Neither is it sufficient to support stage gate decisions by innovators that may cost, save or generate millions of dollars for their organizations.

Furthermore, the information is unable to evolve into knowledge when there is a lack of effort to standardize the vocabulary. To date, the existing commercial sources have also not taken a lead in the area, either due to a lack of resources, industry expertise, content depth and breadth, or editorial rigor.

Simply identifying and documenting new biomarkers is not the issue. What is more important, and difficult, is compiling the data from all its disparate sources into usable formats, and then comparing the relative values of each biomarker that can be used to determine the same effect or physiological activity.

Researchers must learn from the database, the degree to which they can trust the biomarkers to support their work.

An ideal biomarkers initiative needs to be based on in-depth interviews with a number of pharmaceutical, biotechnology and diagnostic companies, talking to both senior management and business development specialists, and the front line of discovery at the bench.

A database (eg, Thomson Reuters' BIOMARKER center) should form a repository of knowledge covering the different uses of biomarkers that are actively being researched or employed. It should incorporate those uses that have been discontinued.

Each record includes the biomarker's name, classifi cation, biological entities/ processes involved, associated drugs, roles or utilities, measurement techniques, development status of diagnostic kits and validation status. It places this knowledge in context, enabling users to assess at a glance the relative importance of different biomarkers. It also indicates how much an organization can put its trust in the biomarker results it is getting.

Supporting contextual information for core biomarker data includes related literature, patents, genomics/targets, drugs and biologics, companies or research institutions, toxicology and clinical studies. The database enriches each record by retrospectively searching the literature and providing links to all source documents.

------------------------------------------------------------

An Intermediary Between Treatment and Disease

'Biomarker' is a good example of a term whose dictionary definition is not keeping pace with the word's changing significance in the real world. Originally, it referred to such physiological indicators as body temperature, blood pressure or heart rate that signaled an imbalance in the body-direct, evidential symptoms of disease. Later, the term took on the additional meaning of detectable foreign substances such as radioactive isotopes whose passage through the system could indicate problems with specific organs or body functions.

Today, a biomarker can more precisely defined as a blood-based test, gene sequence or mutation, mRNA expression profile or tissue protein that can be used to provide evidence of the state of an organism.

The US National Institutes of Health Workshop in December 1998, published in Biomarkers And Surrogate Endpoints: Preferred Definitions and Conceptual Framework (Clinical Pharmacology & Therapeutics, Volume 69, No 3, 2001), calls a biomarker "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention." The presence of a specific antibody in the blood, for example, might indicate a specific infection. The important point is that the biomarker is both objective and measurable.

Once the association between the biomarker and the disease is clearly established, one can be used to signal the other, to a high degree of certainty. Changes in the prevalence of a biomarker in the organism can immediately and reliably signpost the patient's response to treatment, whether beneficial or toxic.

In preventative medicine, by monitoring their blood glucose levels, diabetics can manage their disease and avoid exacerbating its symptoms: the biomarker is an intermediary between the disease and the patient's behavioral regime.

------------------------------------------------------------