Biomarkers are poised to become “one of the major drivers of pharmaceutical research and development in the 21st Century”, with potential to stimulate innovation, improve the efficiency of clinical trials, target therapy more accurately and reduce costs both for innovators and healthcare payers, a new report says.

But so far researchers have only scratched the surface of biomarker potential, it warns. Moreover, commitment from pharmaceutical innovators is patchy and regulatory authorities remain conservative about accepting biomarkers as primary evidence for drug approval. Without more determined efforts to validate biomarkers, the report says, there is a danger that researchers will lose faith and attention will shift elsewhere.

Thomson Scientific (Thomson Reuters), which published the white paper on Establishing the Standards in Biomarker Research, has a personal stake in these issues, having launched its own initiative to collate and standardise the full spectrum of available information on biomarkers in what it calls “a definitive global biomarkers database”.

This will “form a repository of knowledge covering the different uses of biomarkers that are actively being researched or employed, and those uses that have been discontinued”, Thomson Scientific says.

The white paper defines a biomarker 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 key point, it adds, is that a biomarker is both objective and measurable.

While most scientists already use a core set of biomarkers, this is “insignificant compared to the thousands of biomarkers that may exist and have yet to be discovered, documented or quantified”, the report notes. Already scientific understanding of the role of biomarkers is growing in almost every therapy area, but most rapidly in oncology, cardiology, neurology and in metabolic, autoimmune and inflammatory diseases.

The possibilities are “immense”, Thomson Scientific believes. Biomarkers may be used:

- to determine the predisposition for disease in a given population, screen for its presence, confirm its diagnosis, assess its severity, predict its response to available therapies and measure its clinical course;

- as targets for drug discovery;

- as a decisive factor in choosing whether or not to continue research on a particular drug candidate;

- to identify early in the development process whether a drug candidate has side-effects that would rule out commercialisation;

- to help make clinical trials more efficient;

- to reduce treatment overheads by optimising dosages and measuring a patient’s response to therapy more quickly and accurately.

Still the best example of how biomarkers can benefit the whole drug cycle, right from the earliest stages of development, is Roche’s Herceptin (trastuzumab) for HER2-positive breast, the report observes. “It was estimated that from the eight-year acceleration of Herceptin’s approval, Roche saved US$35 million in clinical trial costs and generated US$2.5 billion of income, with 120,000 patients gaining access to the drug before they might otherwise have done.”

Non-validated

For all the interest in biomarkers, though, the attrition rate for their development is “undoubtedly” as high as for drug development, the white paper cautions. And unless researchers can secure regulatory approval for associated diagnostic kits and software, a biomarker will remain “non-validated”, meaning it is “unusable for clinical practice or to support the claims made during drug development”.

Research efforts in the field vary widely, the report says. “Some innovators do a great deal of biomarker research, while others do none. Even among the ones the ones that do, most companies lack a separate group charged with the effort.”

The Catch-22, Thomson Scientific warns, is that “while biomarkers remain undervalued by innovators, they will also be undervalued by regulatory authorities, and while regulatory authorities lack confidence in biomarker evidence, innovators will be reluctant to rely on them to support their stage gate decisions.”

During the early stages of drug discovery and development, a product sponsor can use whatever biomarkers it feels are most reliable, regardless of whether or not these have been validated by a regulatory agency, the white paper points out. This also applies, although to a lesser extent, during Phase I and II clinical trials, providing the biomarkers are ethically acceptable.

Once the drug candidate approaches Phase III trials, though, the sponsor “has no choice but to switch to those biomarkers that will be accepted by regulatory authorities as evidence for approval”.

This is where innovation hits a roadblock. “Since very few of the biomarkers that have the potential to be used as indicators of 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,” Thomson Scientific warns.

Far to go

It acknowledges the FDA’s declared commitment to establishing a regulatory framework to help incorporate biomarkers into drug development as part of its Critical Path initiative, as well as parallel efforts by the European Medicines Agency and by Japan’s Ministry of Education, Culture, Sports, Science and Technology and its Ministry of Health, Labour and Welfare.

Nonetheless, the FDA has also stated that “much development work and standardisation of the biological, statistical and bioinformatics methods must occur before these techniques can be easily and widely used”.

According to Thomson Scientific, the FDA “rarely has an issue accepting biomarker data as evidence of a secondary clinical endpoint, but accepting them as evidence of a primary endpoint is quite a 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, telling the innovator that the primary endpoint must be clinically relevant to the disease and the patient’s well-being”.

Recent history has shown that biomarkers can be fast-tracked to approval where the need arises, the report notes. “With minds sharpened by the explosion in AIDS, it took only a few years of intensive search for a biomarker to combat HIV to accept CD4 cell counts as a validated primary endpoint.”

If gaining acceptance for biomarkers is perceived as “an enormous uphill battle, taking many years and countless millions of dollars”, and researchers are faced with the “Sisyphean” task of negotiating an intransigent regulatory agency, “researchers are likely to tire of the effort”, Thomson Scientific suggests. “The trend will then be to shift focus elsewhere.”