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Expanding Phase IV Trials and Use of Biomarkers for Personalized Medicine Can Help Reduce Drug Risks

Wed, 01/24/2007 - 3:57am

By Mario R. Ehlers, M.D., Ph.D.

How do we get to that ideal of personalized medicine, “The right drug at the right time for the right patient”? And, while we’re working on the “right” drug, let’s look at drugs overall, and ask ourselves this immediate question: How can we make sure that all FDA-approved drugs are not only safe when they are marketed to the public, but will continue to be monitored, ideally in ongoing Phase IV clinical trials, to ascertain their longer-range effects?

By now it has become common knowledge, not only in our industry but among the lay public, that the safety of the nation’s prescription drug supply is seriously compromised. There is no longer any doubt, nor should there be, that we in the industry need to take serious measures, as quickly as possible, to reverse this epidemic. One need only consider the high profile recall of the arthritis drug Vioxx, which its manufacturer pulled from the market after it was shown to double the risk of heart attack and stroke, or the adverse effects warnings on prescription medications, including most recently Vioxx, Celebrex and Bextra. Just this past 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. Safety concerns have likewise recently 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.

Why have so many pharmaceutical medications been linked with health risks in recent years, and who or what is to blame? Worth reading: the editorial, titled “Blueprint for a Stronger Food and Drug Administration,” by Doctors Curfman, Morrissey and Drazen, that ran in the Oct. 26, 2006 New England Journal of Medicine. In that same issue, Bruce Psaty, M.D., Ph.D., and Sheila Burke, M.P.A. and R.N., wrote an article, “Protecting the Health of the Public—Institute of Medicine Recommendations on Drug Safety,” in which they claim that: “in the current model, drugs are rapidly evaluated before approval and are often aggressively marketed afterward.”

The authors also go on to state, and I think they express it perfectly: “The approval process does not represent a singular moment of clarity about the risks and benefits associated with a drug — pre-approval clinical trials do not obviate continuing formal evaluations after approval. However, the approval decision is a critical juncture in a product’s lifecycle because it releases a drug to the market, where the public will gain broad exposure to it. In a strengthened drug safety system, that juncture should mark the beginning of another important stage in the lifecycle, when regulators, sponsors, health insurers, health care providers, and independent researchers actively pursue and manage emerging knowledge about risk-benefit relationships and uncertainty and they communicate that knowledge to patients, health care providers, and health care organizations in a timely manner.”

Based on my years of experience in the biopharmaceutical industry, I consider the FDA overall to be extremely rigorous in their standards for drug safety during the approval process. But no matter how carefully the FDA and the drug companies themselves 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, we cannot accept even low risk as a given. There are actions that legislators and drug-development scientists can take to minimize serious health risks associated with pharmaceutical agents. This can also be accomplished without unduly delaying the development of new medical treatments. These measures fall into two categories:

Greater FDA Control After 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; 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. 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 Consumers Who Are At-Risk. Taking the logic of this first category further, we must encourage, hopefully even mandate, the continuation of Phase IV trials, in order to monitor longer range results that can show us where patient vulnerabilities may show up, and if they do, in which specific groups or types of patients. This information can then be used to help us create personalized drugs, based on biomarkers, that meet the needs of these patients.

One extremely promising result of our greater understanding of human genetics and biology is the increased use of biomarkers. These biological indicators can be used to measure the progress of disease or the effects of treatment, for both drug discovery and development. The biomarker hemoglobin A1C, for example, shows how well a diabetes drug is controlling blood glucose. Biomarkers are being used today, in every therapeutic area, during the drug discovery phase.

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 health-care 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.

It will be years before these biomarkers become available, but they are already causing excitement, and virtually every major drug and biomedical company is now engaged in biomarker research. The companies collect genetic information from patients, via blood samples, at clinical trials. The FDA, which recently issued guidelines on performing these procedures, is encouraging the collection of such genetic material toward further research on the new science of “pharmacogenomics,” the link between specific genetic profiles and the effects of drugs. Champion diagnostics is now moving us closer to our ultimate goal: true personalized medicine.

With greater continued monitoring and control of drugs already on the market by the FDA, and continued advances in biomarker research that brings us closer to personalized medicine, we can, in the not too distance future, greatly reduce the risk of serious side effects for the millions of people who take these medications, and ensure that the needs of people with specific, individual conditions are met, safely and effectively, with “the right drugs at the right time for the right people.”

About the author: Dr. Ehlers is chief medical officer of Seattle-based Pacific Biometrics, Inc., a central laboratory supporting drug and diagnostics development.

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