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UC Davis Health System

UC Davis Health System

Containing the high host of drug therapies for chronic disease

An alternative approach

pills N-of-1 trials are single-patient, randomized, double-blinded, multiple crossover comparisons of an active drug against an alternative drug or placebo.

An alternative method for determining the best drug therapy for managing chronic disease could reduce treatment costs or give patients more immediate relief than other common approaches typically approved for use by managed care and health insurance companies, a study by researchers at UC Davis School of Medicine has concluded. Their study, "N-of-1 Trials of Expensive Biological Therapies — A Third Way?" appeared in the May 2008 issue of the Archives of Internal Medicine.

The investigators developed an economic model to evaluate the costs of three clinical strategies that typically doctors use to treat rheumatoid arthritis: stepped care, open access and an "n-of-1 trial." They wanted to explore whether the n-of-1 trial represented a way to balance the interests of patients with those of payers when establishing policies regarding the use of expensive drugs.

N-of-1 trials are single-patient, randomized comparisons of an active drug against an alternative drug or placebo. Such trials are feasible when a condition being studied is chronic or recurrent, and the costs of treatment very high. In the past 20 years, such trials have been used to evaluate therapies ranging from pulmonary disease to fibromyalgia and osteoarthritis.

During an n-of-1 experiment, a patient is given one treatment and then another, in random sequence, with all symptoms and side effects carefully noted. At the end of the trial period, both patient and doctor are able to determine, with a high degree of confidence, which medicine works better for that particular individual.

For both clinical and economic reasons, managed care organizations typically require "stepped care" experiments for expensive drug therapies used in chronic illnesses such as rheumatoid arthritis. Physicians and patients must first try more established and less expensive drugs before stepping up to more costly biopharmaceuticals.

Dr. Richard Kravitz"Our model suggests an alternative approach that can help patients and their physicians identify a beneficial therapy in a timely and cost-effective manner."
— Richard Kravitz, study lead author

Immediate, or "open," access is another option, wherein a patient has the ability to choose any appropriate therapy regardless of cost considerations.

"A stepped-care policy can be appropriate in many circumstances," said Richard Kravitz, professor of internal medicine and lead author of the study. "However, it also prompts questions from patients about why they can't have open access to a particular medicine right away. Our model suggests an alternative approach that can help patients and their physicians identify a beneficial therapy in a timely and cost-effective manner."

For their study, the UC Davis investigators modeled two disease-modifying anti-rheumatic drugs — methotrexate and etanercept — that are used to avert joint deformity and dysfunction. In the stepped-care plan for rheumatoid arthritis, hypothetical patients took the less expensive drug, methotrexate, for 13 weeks. If that treatment proved successful, the patients would continue with the drug for three years. If methotrexate was inadequate, entanercept, which is self-injected once or twice weekly and can cost approximately $20,000 per year, was added.

With an open access plan, patients immediately would begin with the costlier etanercept and, after 13 weeks, could add other therapies if the initial therapy didn't result in relief.

medications The n-of-1 approach used a 44-week, double-blind clinical trial, alternating each drug in a series of 8-week treatment episodes.

The n-of-1 approach used a 44-week, double-blind clinical trial, alternating each drug in a series of 8-week treatment episodes. UC Davis investigators found that the n-of-1 option, while 15 percent more expensive than stepped care, was 47 percent cheaper than open access to the drugs. The n-of-1 approach also potentially allows patients and their physicians to make more informed decisions about treatment selection because it tests a drug's efficacy earlier in process.

"It appears that n-of-1 trials offer a way to balance clinical judgment, consumer choice and pharmaceutical cost containment in some circumstances," added Kravitz. "Stepped care, although sensible in many circumstances, may seem too restrictive to consumers. And as prescription drug costs continue to increase faster than the overall rate of health-care inflation, new methods for evaluating the effectiveness of treatment in individual patients are needed."

In addition to Kravitz, the study team included Naihua Duan, professor of biostatistics at Columbia University Medical Center, and Richard H. White, professor of general medicine at UC Davis School of Medicine. The team noted that more studies are needed to determine the acceptability, safety and broad applications of what they view as a promising approach to care.