Sweeping Changes Needed for US Drug Safety System

Pharmacology Watch

In response to several high-profile drug misadventures including the rofecoxib (Vioxx®) withdrawal from the market, the FDA's Center for Drug Evaluation and Research (CDER) asked the Institute of Medicine (IOM) to assess the drug safety system in the United States. The recommendations, published in the October 26 New England Journal of Medicine, call for sweeping changes, especially in the post-marketing surveillance of new drugs.

The report suggests that the FDA has acted to accelerate drug approvals without ensuring the safety of these drugs once they are approved and on the market. Direct-to-consumer advertising is also partially to blame, especially when aggressive marketing campaigns lead to sudden widespread use of a new drug. Chronic under funding and a poor work environment at the FDA are also partially to blame. But the biggest culprit is the lack of an effective mechanism of continued evaluation of new drugs once they're on the market, which currently amounts to little more than reports of adverse events from practitioners. The IOM's report recommends changes in the FDA's committee structure, which strengthens conflict-of-interest restrictions and recommends that the FDA commissioner be appointed for a fixed term of 6 years. They also recommend labeling new drugs with a symbol such as a black triangle for up to 2 years to signify "the uncertainty associated with new drugs" and a moratorium on direct to consumer advertising during that period. Five years after a drug's launch, the FDA should perform a review of the risk/benefit status of all approved drugs (N Engl J Med. 2006;355:1753–1755).

An accompanying editorial points out that much of the money provided to the CDER is for drug approval, and much of it derives from industry, whereas little funding is earmarked for monitoring of the safety of drugs after they've been approved and introduced onto the marketplace. The editorialists recommend that all clinical trials beyond phase I must be registered in the public database, as has been recommended previously. The editorial also endorses the black triangle indication in the first 2 years after the drug's approval in a moratorium on direct-to-consumer advertising during that time. Most importantly, the editorialists ask for better funding and more transparency in the FDA, and urges Congress to implement the recommendations (N Engl J Med. 2006;355:1821).

Antiaging Supplements Proven Ineffective

Dehydroepiandrosterone (DHEA) and testosterone are not effective antiaging supplements, according to 2 new studies. Both compounds have been widely marketed as antiaging supplements. The first study from the New England Journal of Medicine was a 2-year, placebo-controlled, randomized, double-blind study involving both women and men.

Among the men, 29 received DHEA, 27 received testosterone, and 31 received placebo. Among women, 27 received DHEA and 30 received placebo. After 24 months the men showed no significant effect of DHEA on body- composition measurements. Neither DHEA nor testosterone affected oxygen consumed per minute, muscle strength, or insulin sensitivity. Testosterone resulted in a slight increase in fat-free mass, and both DHEA and testosterone resulted in an increase in bone mineral density at the femoral neck. Women who received DHEA had an increase in bone mineral density at the ultradistal radius. There was no difference in quality-of-life issues in either group with any intervention. The authors conclude that neither DHEA nor low-dose testosterone replacement in elderly people has physiologically relevant beneficial effects on body composition, physical performance, insulin sensitivity, or quality of life (N Engl J Med. 2006; 355:1647–1659).

The second study was also a double-blind, randomized, controlled trial that included a hundred men age 70 and over. Subjects were randomized to receive DHEA 50 mg/d, the anti-estrogen atamestane 100 mg/d, the combination of the 2, or placebo for 36 weeks. No differences were found in either treatment arm compared with placebo on a battery of tests, which included isometric grip strength, leg extensor power, and physical performance (J Clin Endocrinol Metab. 2006;91:3988–3991).

The Three Most Common Culprits of ADE

Three drugs are responsible for a third of the estimated 700,000 outpatient adverse drug events per year in this country, according to a new study. A collaborative effort of the FDA, CDC, and US Consumer Chronic Safety Commission developed the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project several years ago to assess the risk of adverse drug events (ADEs) in the outpatient setting. During the 2-year study period, 21,298 ADEs were reported that resulted in patients presenting to the emergency departments of the 63 reporting hospitals. This extrapolates to over 700,000 cases annually in this country. Individuals age 65 or older were more likely than younger individuals to suffer an ADE. Drugs for which regular outpatient monitoring is used to prevent toxicity accounted for 41.5% of hospitalizations, and 50% of hospitalizations were in people age 65 and older. Of those drugs, insulin, warfarin, and digoxin were responsible for one in 3 estimated ADEs treated in emergency departments. The authors conclude that adverse drug events are an important cause of morbidity in the United States, especially among the elderly, and that ongoing population-based surveillance may help target prevention strategies (JAMA. 2006; 296:1858–1866).

New Guidelines for Lyme Disease Prevention

The Infectious Disease Society of America has issued new guidelines for Lyme disease (LD) prevention. Of note, guidelines state that routine use of antimicrobial prophylaxis or serologic testing is not recommended after a recognized tick bite; however, a single dose of doxycycline 200 mg may be given to adults and children over the age of 8 if 1) the attached tick is recognized as a potential carrier of LD and has been attached for least 36 hours; 2) the dose can be given within 72 hours of tick removal; 3) the patient is in an endemic area; 4) doxycycline is not contraindicated. Testing of ticks is not recommended. Even if patients have been prophylaxed, they should be monitored for signs and symptoms of tick-borne illness for up to one month (Clin Infect Dis. 2006:43—published online October 2, 2006).

FDA Actions

The FDA has approved a new agent for the treatment of hepatitis B infections. Telbivudine (Tyzeka™), from Novartis, has been approved for the treatment of adults with chronic hepatitis B infections. In clinical trials, the drug was shown to suppress replication of hepatitis B virus and reduce liver inflammation.

The FDA has approved Merck's sitagliptin (Januvia™), a new oral antidiabetic for the treatment of type 2 diabetes. The drug is a DPP-4 inhibitor, a new class of medications that prolongs the action of incretin hormones, resulting in improved glycemic control. The drug is approved for monotherapy or as add-on with metformin or a thiazoldinedione. Sitagliptin has the theoretical advantages of not causing weight gain or increasing the risk of hypoglycemia. It is supplied as a 100 mg tablet that is given once a day.


This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5431. E-mail: jennifer.corbett@ahcmedia.com.