Evaluations may be based on faulty assumptions

Faulty assumptions in economic models used to evaluate the cost-effectiveness of prescription drugs may incorrectly favor more expensive drugs, according to a new study published Sept. 9 in the Journal of Managed Care Pharmacy.

In the study, researchers at Express Scripts, a pharmacy benefit manager based in St. Louis, substituted actual data in place of model assumptions and discovered that economic models used to compare ulcer treatments overstated the cost-effectiveness of more expensive treatments.

The researchers looked at treatments that combined antibiotics with either a generic bismuth drug or a more expensive branded proton pump inhi-bitor. The more economical bismuth-based treatment was actually the most cost-effective.

The models had incorrectly assumed that antibiotic resistance and patients failing to take their medicine would compromise the effectiveness of the cheaper bismuth-based treatments. The models also overestimated physician, laboratory, and hospitalizations costs triggered by disease recurrence after treatment.

"Key model assumptions were largely unsupported by either evidence or expert opinion," says Brenda R. Motheral, PhD, a study co-author and vice president for outcomes research at Express Scripts.

The findings reaffirm the oft-expressed need for ongoing examination of the validity of economic models used to evaluate and compare the cost effectiveness of prescription drugs, she adds.

FDA, Customs finds potentially dangerous drug shipments

A recent series of spot examinations of mail shipments of foreign drugs to U.S. consumers conducted by the U.S. Food and Drug Administration (FDA) and U.S. Customs and Border Protection (CBP or Customs) revealed that these shipments often contain dangerous unapproved or counterfeit drugs that pose potentially serious safety problems.

This joint operation was carried out to help the FDA and CBP target, identify, and stop counterfeit and potentially unsafe drugs from entering the United States from foreign countries via mail and common carriers. It also was designed to help the FDA and CBP assess the extent of this problem.

These "blitz" exams were conducted in the Miami and New York (JFK) mail facilities from July 29-31, 2003, and the San Francisco and Carson, CA, mail facilities from Aug. 5-7, 2003, to obtain a representative picture of products entering the United States. In each location, packages shipped by international mail through U.S. Postal Service facilities over a three-day time span were examined. For the purposes of these blitzes, the FDA and CBP identified, through review of historical data and experience, packages likely to contain drug products.

Approximately 100 parcels (each of which may have contained multiple drug products) per day per facility were selected based upon their country of origin and historical experience. They were subsequently opened by the CBP and jointly examined by both agencies. The CBP held those in violation of CBP provisions. The FDA detained those in violation of FDA regulations.

Of the 1,153 imported drug products examined, the overwhelming majority — 1,019 (88%) — was in violation because they contained unapproved drugs. Many of these imported drugs could pose clear safety problems. These problems included drugs with inadequate labeling, drugs inappropriately packaged, drugs withdrawn from the market, drugs with dangerous interactions, and controlled substances.

These drugs arrived from many countries. For example, 15.8% (161) entered the United States from Canada; 14.3% (146) from India; 13.8% (141) from Thailand; and 8% (82) from the Philippines. The remaining entries came from other countries.

Color in enteral feeding tube linked to toxicity, death

The FDA is warning health care professionals of several reports of toxicity, including death, temporally associated with the use of FD&C Blue No. 1 (Blue 1) in enteral feeding solutions. In these reports, Blue 1 was intended to help in the detection and/or monitoring of pulmonary aspiration in patients being fed by an enteral feeding tube.

Reported episodes were manifested by blue discoloration of the skin, urine, feces, or serum, and some were associated with serious complications such as refractory hypotension, metabolic acidosis, and death. Case reports indicate that seriously ill patients, particularly those with a likely increase in gut permeability (such as patients with sepsis), may be at greater risk for these complications. Because these events were reported voluntarily from a population of unknown size, it is not possible to establish the incidence of these episodes.

From the reports, it appears that neither the concentration nor the total amount of Blue 1 used in the enteral feeding solutions was unusually high compared to other patients in whom no toxicity was observed. Thus, if there is a causal relationship between the dye and the serious outcomes, there could be underlying patient-related factors that allow significant absorption of Blue 1 in some enterally fed patients.

The FDA is aware of 20 cases from reports in the scientific literature or in FDA post-marketing adverse event reports as of September associating the use of blue dye in tube feedings with blue discoloration of body fluids and skin, as well as more serious complications. There have been 12 reported deaths and one case with an unknown outcome.

In more than 75% of all reported cases, patients had a reported history of sepsis (and therefore likely altered gut permeability) before or during systemic absorption of Blue 1. Time of onset of toxicity from first use of Blue 1 varied from several hours to 20 days of continuous use in enteral feedings.

The FDA says it will continue to closely monitor reports for additional events.

Antiviral agent causes adverse effects in SARS patients

A study published in the Oct. 15 issue of the journal Clinical Infectious Diseases says that ribavirin, the drug doctors used to fight severe acute respiratory syndrome (SARS) in Canada and Hong Kong may not be the best choice for fighting the disease. Although the antiviral agent has previously been used for treating hepatitis C and respiratory syncytial virus (RSV) pneumonia, it showed an unusual number of adverse effects when used on patients with SARS. Ultimately, this led to an increase of prolonged hospital stays.

Although there are few data available from controlled experiments, Canadian hospital reports suggest that the risks of ribavirin outweigh the benefits. The most common adverse effect was hemolytic anemia, which occurred to some extent in 61% of patients reviewed, 28% of whom required blood transfusions. Other effects were electrolyte disturbances, mainly a decrease in calcium and magnesium levels.

Health officials in Canada have restricted the use of ribavirin as treatment for SARS, but the drug still is being used in Hong Kong, on the grounds that it has the ability to modulate the immune system in beneficial ways. Nevertheless, alternative drugs are now being explored in Hong Kong. Other potential candidates are specific types of human interferon, which have shown promising activity in vitro as well as in SARS patients, and have low adverse effect profiles.