September 1, 2009 (Vol. 29, No. 15)
As Evidence of Benefits Grows, Revision of Laws, Policy, Education, and Clinical Practices Is Needed
Personalized medicine may be considered an extension of traditional approaches to understanding and treating disease. Physicians have always used observable evidence to make a diagnosis or prescribe a treatment tailored to each individual. In the modern conception of personalized medicine, the tools provided to the physician are more precise, probing not just the visually obvious, such as a tumor on a mammogram or the appearance of cells under a microscope, but the very molecular makeup of each patient.
A profile of a patient’s genetic variation can guide the selection of drugs or treatment protocols that minimize harmful side effects or ensure a more successful outcome. It can also indicate susceptibility to certain diseases before they become manifest, allowing the physician and patient to set out a plan for monitoring and prevention.
The ability to profile the structure, sequence, and expression levels of genes, proteins, and metabolites is redefining how we classify diseases and select treatments, allowing physicians to go beyond the one- size-fits-all model of medicine to make the most effective clinical decisions for each patient.
It is an approach that is well suited to the medical challenges faced in the 21st century. Although we have prevailed over many of the diseases that have plagued humanity throughout the ages, what remains are diseases of greater complexity: diabetes, cancer, heart disease, and Alzheimer’s disease. They are not caused by a single gene or a single event but by a combination of genetic and environmental factors, and they tend to be chronic, placing a heavy burden on the healthcare system. Personalized medicine provides the tools needed to better manage chronic diseases and treat them more effectively.
We can now point to real-world applications of almost every aspect of personalized medicine’s promise: Genetic profiles can better discern different subgroups of breast cancer, guiding physicians to select the best treatment protocol or, in some cases, forego the expense and risks of chemotherapy altogether; and tests detecting variation in the way individuals metabolize warfarin can help determine the right dose for a patient, navigating the narrow therapeutic passage between reducing risk of clots, and triggering internal bleeding.
Also, a test for mutations in the genetic coding for an enzyme can help physicians select the most effective drug for a colon cancer patient from an expanding pharmacopoeia of choices, avoiding a costly and protracted trial-and-error approach that can leave the patient suffering needlessly from adverse effects or losing precious time in battling the disease.
As evidence of the benefits continues to grow, an infrastructure of laws, policy, education, and clinical practice is building around personalized medicine to support its use:
- Medical institutions across the country have announced their commitment to putting personalized medicine into practice through dedicated centers or statewide initiatives.
- Personalized medicine approaches are becoming best practice in hospitals to ensure that patients with serious conditions such as cancer are given optimum therapy from the start.
- The regulatory system is integrating genetic testing into the labels of pharmaceutical products, ensuring that a drug is administered in a way that minimizes the risk of adverse effects and improves the chances of effective treatment.
- Nearly every major pharmaceutical development project is incorporating information on genetic variation and its effects on the safety and effectiveness of the candidate drug.
- Personalized medicine applications have extended beyond cancer to improve treatments in cardiovascular disease, infectious diseases, psychiatric disorders, and transplantation medicine.
- Several of the nation’s leading medical schools are launching genomics-based medical education programs to train the next generation of care providers.
- The American Association of Health Plans has advocated policy encouraging genetic testing and preventive care, while several large private insurers have begun paying for genetic tests identifying presymptomatic high-risk populations.
- The U.S. Department of Health and Human Services, the President’s Council of Advisors in Science and Technology, and the Personalized Medicine Coalition have defined wide-ranging policy recommendations for personalized medicine; a genetic privacy law has been passed, and other legislation supporting personalized medicine has been introduced in the U.S. Senate and House of Representatives.
Edward Abrahams, Ph.D.
Clinical Applications
Ultimately, the success of personalized medicine will rise or fall on its ability to demonstrate its value to the healthcare system, to the industries that develop its products, and to patients. The promise of personalized medicine, for which tangible evidence already exists, includes the ability to:
- Shift emphasis in medicine from reaction to prevention,
- Enable the selection of optimal therapy and reduce trial-and-error prescribing,
- Make the use of drugs safer by avoiding adverse drug reactions,
- Increase patient compliance with treatment,
- Reduce the time and cost of clinical trials,
- Revive drugs that are failing in clinical trials or were withdrawn from the market,
- Reduce the overall cost of healthcare.
Personalized medicine introduces the ability to use molecular markers that signal the risk of disease or its presence before clinical signs and symptoms appear. This information underlies a healthcare strategy focused on prevention and early intervention, rather than a reaction to advanced stages of disease. Such a strategy can delay disease onset or minimize symptom severity.
One example is a test used to look for BRCA1 and BRCA2 genetic mutations indicating a hereditary propensity for breast and ovarian cancer.
Women with BRCA1 or BRCA2 genetic risk factors have a 36% to 85% lifetime chance of developing breast cancer, compared with a 13% chance among the general female population.
For ovarian cancer, women with certain BRCA1 or BRCA2 gene mutations have a 16% to 60% chance of disease, compared with a 1.7% chance among the general population. The BRCA1 and BRCA2 genetic test can guide preventive measures such as increased frequency of mammography, prophylactic surgery, and chemoprevention.
Over 1,300 genetic tests exist that signal inherited susceptibility to conditions as wide-ranging as hearing loss and sudden cardiac arrest. While not every test has a therapeutic option, a genetic diagnosis often permits targeted prevention or mitigation strategies.
On average, a drug on the market works for only 50% of the people who take it. The consequences in terms of quality and cost of care are significant, leaving patients to contend with their disease and their medical bills as they switch from one drug to another until they find an effective therapy. Studies have linked differences in response to the differences in genes that code for the drug-metabolizing enzymes, drug transporters, or drug targets. The use of genetic and other forms of molecular screening allows the physician to select an optimal therapy the first time and avoid the frustrating and costly practice of trial-and-error prescriptions.
The ability to profile genes, proteins, and metabolites is redefining how we classify diseases and select treatments.
© Gernot Krautberger
Make Drugs Safer
According to a review of several studies, about 5.3% of hospital admissions are associated with adverse drug reactions (ADRs). Many ADRs are the result of variations in genes coding for the cytochrome P450 (CYP450) family of enzymes and other metabolizing enzymes. These variants may cause a drug to be metabolized more quickly or slowly than in the general population.
As a result, some individuals may have trouble eliminating a drug from their bodies, leading in essence to an overdose as it accumulates, while others eliminate the drug before it has a chance to work. The consequences of not considering variation in these genes when dosing can range from futility to unpleasant or even fatal side effects.
Patient Compliance
Patient noncompliance to treatment leads to adverse health effects and increased costs. When personalized therapies prove more effective or present fewer side effects, patients will be more likely to comply with their treatments. The greatest impact could be for the treatment of diseases such as asthma and diabetes, in which noncompliance commonly exacerbates the condition. At least one study supports this point.
Inherited forms of hypercholesterolemia (high cholesterol) can increase the risk of myocardial infarction before the age of 40, more than 50-fold in men and 125-fold in women. Conventional monitoring of cholesterol levels can catch the condition early, but genetic testing offers additional benefits.
In addition to detecting the condition before there are observable signs of disease, knowledge of a genetic predisposition for hypercholesterolemia provides patients with a powerful incentive to make lifestyle changes and to treat their condition seriously. Patients with a genetic diagnosis have shown more than 86% adherence to their treatment program after two years compared to 38% prior to testing.
Improving Clinical Trials
Developing a new drug is a costly and lengthy process. Theoretically, the use of pharmacogenomic data, or information about how patients’ genes affect their drug responses, could reduce the time and cost of drug development in addition to reducing the rate of drug failures by allowing researchers to focus on subsets of patient populations. Using genetic tests, researchers could select patients for studies, using those most likely to respond or least likely to suffer side effects. Enriching the clinical trial pool, as this approach is called, could reduce the size, time, and expense of clinical trials.
The cost of healthcare in the U. S. is on an unsustainable upward climb. Incorporating personalized medicine into the fabric of the healthcare system can help resolve many embedded inefficiencies, such as trial-and-error dosing, hospitalization of patients who have severe reactions to a drug, late diagnoses, and reactive treatment.
Specific examples of personalized medicine are generating tangible results about their economic benefit. Authors of a recent study exploring potential healthcare cost savings from using genetic testing estimated that the use of a genetic test to properly dose warfarin could prevent 17,000 strokes and 85,000 serious bleeding events each year and avoid as many as 43,000 visits to the emergency room. If the two million people that start taking warfarin each year were to be tested at a cost of $125 to $500 per patient, the overall cost savings to the healthcare system would be $1.1 billion annually.
Edward Abrahams, Ph.D. (eabrahams@personalized
medicinecoalition.org), is executive director of the Personalized Medicine Coalition. This article is excerpted from the second edition of “The Case for Personalized Medicine”. Go to www.personalizedmedicinecoalition.org for a complete copy of the report.
