Study Concludes Premarketing Drug Trials Underpowered

Pharmacology Watch

The phrase, "Never be the first to prescribe a new drug" may be sage advice, according to a new study. More than 10% of new drugs (56 of 548) approved between 1975 and 1999 were withdrawn from the market or given black box warnings indicating serious side effects. Half of the withdrawals occurred in the first 2 years of the drug’s introduction while half of the black box warnings occurred within the first 7 years. A recent study concluded that premarketing drug trials may be underpowered to detect serious adverse drug reactions, and that many drugs have limited postmarketing follow-up. It is only after the use of these medications is expanded to large numbers of patients that trends are discovered. This study suggests that the FDA should consider raising its threshold for approving new drugs, especially when safe and effective therapies already exist. They also suggest that clinicians should be wary of new drugs and should immediately report adverse drug reactions to Medwatch, the FDA’s adverse drug reporting program (JAMA. 2002;287:2215-2220). In an accompanying editorial, physicians from the FDA said that many of the warnings were the result of ongoing clinical studies such as the Cardiac Arrhythmia Suppression Trial. In general the FDA’s evaluation process is improving. They do however agree that physicians should carefully contemplate prescribing a new drug—especially when safe alternatives are available (JAMA. 2002;287:2274-2275).

Sildenafil to Receive Competition

Sildenafil (Viagra-Pfizer) may soon be in for some tough competition as Lilly’s tadalafil (Cialis) nears approval. The drug has received an approvable letter from the FDA for the treatment of erectile dysfunction and needs only completion of additional clinical pharmacology studies, manufacturing inspections, and finalization of labeling to receive approval. Tadalafil is reported to have a quicker onset of action than sildenafil. Lilly, which is marketing the drug in partnership with Seattle-based Icos pharmaceuticals, feels that a 2003 launch is likely.

New Thrombolytic Therapy Study

Patients with pulseless electrical activity do not benefit from thrombolytic therapy, according to a new study. A total of 233 patients with cardiac arrest and pulseless electoral activity were randomized to receive tissue plasminogen activator or placebo along with CPR. The proportion of patients returned a spontaneous circulation of 21.4% in the t-PA group vs. 23.3% in the placebo group (P = 0.85; 95% confidence interval, -12.6-8.8). The basis of study was assumption that coronary thrombosis or pulmonary thromboembolism are common causes of acute cardiac arrest and pulseless electrical activity. The study, however, found no benefit of fibrinolyis with t-PA in these patients (N Engl J Med. 2002;346:1522-1528).

COX-2 Findings Criticized in BMJ

An editorial in the June 1 edition of the British Medical Journal severely criticizes the findings of the Celecoxib Long-term Arthritis Safety Study (CLASS) trial (JAMA. 2000;284:1247-1255). That study, which was sponsored by, and has been widely publicized by, celecoxib’s manufacturer Pharmacia, showed that the COX-2 inhibitor celecoxib, when compared with traditional nonsteroidal anti-inflammatory drugs (NSAIDs), was associated with the lower incidence of symptomatic ulcers and ulcer complications. The authors of the editorial argue however that the CLASS data reported in the JAMA article actually referred to the combined analysis of the results of the first 6 months of 2 separate and longer trials, both of which had different protocols, outcomes, and durations. With re-review of the data, almost all ulcer complications in the second half of the trial were in users of celecoxib. Also when the pre-defined definition of ulcer complications was used, a nonsignificant trend in favor of diclofenac was found. Perhaps more significantly, the JAMA paper reported only the first 6 months of data, when data up to 12 months were available to the researchers, at which time the rate of ulcer complications for celecoxib was equal to that of traditional NSAIDs. This editorial points out that the VIGOR trial comparing the upper GI toxicity of rofecoxib and naprosyn in patients with rheumatoid arthritis found an unequivocal benefit for the other COX-2 inhibitor, Rofecoxib and over a traditional NSAID (N Engl J Med. 2000;343:1520-1528). The authors point out not only the flaws in the CLASS data, but their disappointment in the use of the data in marketing efforts (BMJ. 2002;324:1287-288).

Salmeterol Aids Pulmonary Edema Victims

The beta adrenergic agonist salmeterol helps protect mountaineers against high-altitude pulmonary edema. Beta agonists, along with causing bronchodilation, also facilitate clearance of alveolar fluid in the lung, the primary cause of high-altitude pulmonary edema. In a recent Swiss study, 37 mountain climbers who were subject to pulmonary edema were randomized to receive salmeterol or placebo in a double-blind fashion. After a rapid ascent to 4500 m, 74% of those in the placebo group developed pulmonary edema vs. 33% in the salmeterol group (P = 0.02). Subjects in the study were also evaluated for nasal transepithelial potential difference, a marker of transepithelial sodium water transport in the distal airways. The results from susceptible individuals were compared to the results from mountaineers not prone to pulmonary edema. The mountaineers prone to pulmonary edema were found to have a low nasal potential difference value. It is speculated that this may also be the case of patients for prone to pulmonary edema from such conditions as congestive heart failure and acute respiratory distress syndrome. It is suspected that this mechanism may be an appropriate target for therapy with inhaled beta agonists (N Engl J Med. 2002;346:1631-1636).

Azithromycin vs. Vitamin C for Bronchitis

Azithromycin is one of the most popular antibiotics for the treatment of upper respiratory tract infections. However, a recent study suggests that it is no more effective than vitamin C in treating acute bronchitis. A total of 230 patients were randomized to receive azithromycin (Zithromax Z-Pack) for 5 days or vitamin C also for 5 days. Patients also received liquid dextromethrophan and albuterol inhalers spacer. After 7 days, 89% of patients in both groups had returned to normal activities. There’s no difference in the incidence of adverse effects. Eighty-one percent of patients reported benefit from the albuterol inhaler. The authors conclude that azithromycin is no better than vitamin C in the treatment of acute bronchitis and suggest that similar studies should be done to identify the best treatment for this disorder (Lancet. 2002;359:1648-1654).

FDA News

The FDA has approved a new angiotensin II receptor blocker (ARB). Olmesartan medoxomil (Benicar—Forest Laboratories) is a once-a-day ARB that is approved for monotherapy or in combination with another antihypertensive. It will be available in 5-, 10-, and 20-mg tablets. It will be the seventh ARB approved for use in this country.

The Nonprescription Drug Advisory committee for the FDA will soon consider omeprazole (Prilosec) for over-the-counter status. AstraZeneca is proposing an over-the-counter 20 mg dose of omeprazole be taken for 14 days for symptoms of frequent heartburn.

The same committee recently proposed loratidine’s (Claritin) switch to OTC for the treatment of urticaria. Final action on loraditine is expected to occur on November 28, 2002.

Drugs receiving expanded indications from the FDA:

Sertraline (Zoloft) has been approved for premenstrual dysphoric disorder, joining its cousin SSRI fluoxetine in having this indication.

QVAR inhaler, a nonfluorocarbon-based beclomethasone inhaler, has been approved for adults and children up to age 12; now the FDA has expanded the indication to children ages 5-11.

The FDA has approved a 35 mg once-a-week dose of residronate (Actonel) for the treatment of osteoporosis. Residronate joins alendronate (Fosamax) with a once-a-week formulation for this indication.

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. Telephone: (404) 262-5517. E-mail: 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.