FDA official: Biomarkers can change the future

Biomarkers may be on the verge of changing medicine, but they need a push, Janet Woodcock, M.D., FDA’s deputy commissioner and chief medical officer, told the Pharmacy and Therapeutics Society recently. The need is to find a new generation of biomarkers to allow individualizing of therapy and integrating such biomarkers into controlled trials. So stated Woodcock in her recent address at the P&T conference in Washington, D.C.

In a report last year, FDA said, “Biomarkers are measurable characteristics that reflect physiological, pharmacological, or disease processes in animals or humans….Techniques as disparate as imaging, serum or genetic assays, or psychological tests can yield biomarkers that are useful in product development.”

Woodcock went on to say, for example, there are a “tremendous number of drugs on the market” that have polymorphic metabolism and “cause all kinds of havoc.” She noted that the FDA has pulled a number of those drugs off the market because of problems. Developers, she said, try to avoid polymorphic metabolism and they seek the traditional one-size-fits-all dosing. But individualized treatment based on metabolism could increase understanding of drugs in trials, reduce adverse events, and have a positive effect on drug development. Despite the lagging status of the field, she said, for some drugs “we are getting tests for metabolism now.

“The cost of running people’s enzymes is going to drop every year according to some pharmacogenetic version of Moore’s law. And pretty soon it’s probably going to be economically highly feasible.” Moore’s law refers to a trend in computer development in which the capabilities of computers will increase exponentially over a short period of time and costs will decline at the same time. In addition, she said, there are currently many diseases that are clinical syndromes: They are defined observationally and “undoubtedly” are really a collection of different pathogenic states. Clinicians are treating all kinds of things under the banner of some disease” which could be identified and monitored through the use of biomarkers.

Advances in how biomarkers are used will allow for much better treatment targeting, Woodcock believes. Among other benefits, cutting out substantially less responsive and unresponsive categories of patients can markedly improve treatment effects.

Double benefit

And, in some cases, there is a sort of double benefit, Woodcock indicated: The subsets of patients who are less responsive to a medication “may also contribute disproportionately to adverse event experiences.”

Woodcock went on to say that “in psychiatry we are working with the NIH [National Institutes of Health], making very aggressive efforts to identify genomic subgroups in depression and psychotic illness. And these groups appear to correlate not only with response to treatment,” she said, but also with what side effects the patients get. If the research goes well over the next several years, she added, it should provide some “extremely beneficial” information for sorting out what treatment groups patients should be in.

Biomarkers could also be a boon to pharmaceutical prevention, where, Woodcock asserted, there has not been much progress beyond vaccination. The barrier for pharmaceutical investment in prevention, she said, has been the benefit-risk assessment of clinical trials. Such research, she noted, must expose many people, possibly for years, to an investigational agent. And many of those people would never have developed the disease. But if biomarkers could identify the people who are at high risk, there would be a much more compelling rationale for trials. Right now, however, the fate of most candidate biomarkers is poor: Only a small number are developed into commercial lab tests and still fewer are actually used in clinical care. The evidence base for particular biomarkers often remains slim or controversial because it has not been adequately researched, she said.

Woodcock noted that there is still “little to no” pharmacogenetically directed dosing used in development. The reason for the lag, according to the FDA official, is that no one is in charge of developing biomarkers. “The diagnostic companies are too poor to develop clinical evidence at those levels needed,” and up to this point the NIH has not done much of this research.

Getting it done

To get the work done, FDA through its “Critical Path Initiative” and other organizations have built several consortia to develop and prove the worth of biomarkers. For example, Woodcock said, the Biomarker Consortium includes FDA, NIH, the Pharmaceutical Research & Manufacturers of America, patients’ groups, and others. The Significant Adverse Event (SAE) Consortium is made up of industry players evaluating the genetic basis of rare SAEs. The Cardiac Safety Consortium includes Duke University, FDA, and industry players studying certain cardiac biomarkers. P&T committees are likely to see some of the research outcomes in the next five years, she predicted, “probably with less than ideal evidence about their performance. But I think there will be an ultimate payoff.”

Woodcock concluded, “We have to move toward a more scientific, mechanistic practice of medicine. The art of medicine is wonderful, but we have to have the evidence base underlying it that can guide us.”

the author is a writer based in the Washington, D.C., area.