Dr. Mario Ehlers discusses how new biomarkers can reduce the risks from pharmaceutical drugs.
The problem of serious physical risks associated with pharmaceutical drugs is not going away. While the arthritis drug Vioxx, pulled from the market by its manufacturer last year after it was shown to double the risk of heart attack and stroke, remains the most high-profile example, a significant number of pharmaceutical medications have been linked with health risks in recent years.
Rezulin, for type 2 diabetes, was taken off the market in 2000 because of its association with severe liver toxicity. This past year, Celebrex and Bextra, in the same class as Vioxx, made headlines for their adverse effects; and in February, sales of the multiple sclerosis drug Tysabri were suspended after it was suspected of triggering a rare brain disease in three patients, two of whom died from the disease. Most recently, safety concerns have emerged about the heart failure drug Natrecor, and doctors at the Cleveland Clinic are considering curtailing its use, after two medical journal studies reported that it increased kidney problems and death rates among patients.
Some people fault the FDA, claiming that the agency does not sufficiently monitor pharmaceutical drugs for safety during clinical trials. Based on my own years of experience in the biopharmaceutical industry, I consider the FDA to be extremely rigorous in their standards for drug safety during the approval process. But no matter how carefully the FDA and drug companies monitor for safety, the potential for a low incidence of serious side effects will always exist: There is simply no way to guarantee that pharmaceutical drugs will ever be entirely risk-free.
That said, there are actions that legislators and drug-development scientists can take to minimize serious health risks associated with pharmaceutical agents. (On the science front, progress is already underway.) What's more, this can be accomplished without unduly delaying the development of new medical treatments. These measures fall into two categories:
Greater FDA Control Following Drug Approval
Although a pharmaceutical drug cannot be marketed without FDA approval, the agency has insufficient control over what happens to a drug after it reaches the market. Federal laws governing drug safety withdrawals are limited and therefore in the event of reported health risks the FDA generally asks manufacturers to withdraw the drug voluntarily. While drug makers almost always comply, there is a question about the completeness and promptness of product withdrawals.
A recent example: In April, the FDA requested that Pfizer, the maker of Bextra, withdraw the drug after reports of some users experiencing serious skin reactions, as well as concerns about cardiovascular risks. On its website, the FDA posted, "Pfizer has agreed to suspend sales and marketing of Bextra in the US, pending further discussions with the agency." Despite widespread reports in the media that the drug was withdrawn, sales of Bextra have been suspended but the drug has not been formally removed.
To prevent the availability of potentially unsafe medications, legislation is needed that will give the FDA greater resources for post-marketing surveillance and unilateral power to withdraw drugs that the agency regards as posing insufficient benefit or serious risk.
Identifying At-Risk Consumers
As the Genome project and other scientific advances have brought about a greater understanding of human genetics and biology, one extremely promising result has been the increased use of biomarkers in drug discovery and development. A biological indicator that can be used to measure the progress of disease or the effects of treatment (the biomarker hemoglobin A1C, for instance, shows how well a diabetes drug is controlling blood glucose), biomarkers are used today during drug discovery in every therapeutic area.
The newest generation of biomarkers, still in its incubation phase, will enable a new treatment paradigm known as theranostics (for "therapeutic" and "diagnostic"). Theranostics involves a tight coupling between diagnostics and therapies, such that a biological indicator determines in advance which patients will respond to a particular treatment. By targeting these patients, the biomarkers favorably alter the risk-benefit profile of pharmaceutical drugs, allowing non-responders to avoid potential side effects unbalanced by therapeutic gain. These biomarkers promise to eliminate much of the uncertainty involved in prescribing medications -- and result in significant healthcare savings.
The best-known theranostic currently on the market is the biomarker for Herceptin, a drug for suppressing tumor growth in patients with metastatic breast cancer, which is used to test biopsy samples of tumors: A sample that tests positive indicates that the patient can be helped by the drug. Given that Herceptin is effective in only about a quarter of patients, the biomarker for this drug is particularly useful.
The next phase of biomarker research, already underway, is to develop biological indicators identifying patients likely to experience adverse effects from a pharmaceutical drug. Not only will such biomarkers reduce the incidence of side effects from medications -- they will also be a means to help keep widely effective, potentially lifesaving drugs available to the public.
Consider the case of Tysabri, the multiple sclerosis drug removed from the market after three users developed brain disease. As a result of the withdrawal, thousands of MS patients who were not adversely affected by the drug nonetheless lost access to it. Once there is a way to target the tiny minority of individuals who cannot safely take a particular drug, the medication can then remain available to the overwhelming majority of patients able to use it without adverse effect. (Biogen Idec, the maker of Tysabri, announced in April that it is conducting a safety review of the drug to determine whether it can be prescribed to certain patients if they are closely monitored.)
It will be years before these biomarkers become available, but there is already much to be excited about. Virtually every major drug and biomedical companies is now engaged in biomarker research. The companies collect genetic information from patients (via blood samples) at clinical trials, and the FDA, which recently issued guidelines on performing these procedures, is encouraging such collection of genetic material toward further research on the new science of "pharmacogenomics," the link between specific genetic profiles and the effects of drugs. Theranostics is taking us closer to what, arguably, is our ultimate goal: true personalized medicine.
Pharmaceutical drugs will never be 100 percent free of risk. But with greater FDA control of drugs already on the market -- and continued advances in biomarker research -- we can greatly reduce the risk of serious side effects for the millions of people who take these medications.
Mario R. Ehlers, MD, PhD, is chief medical officer of Seattle-based Pacific Biometrics, a central laboratory supporting drug and diagnostics development.