By Robert Davidson, M.D., Ph.D.
November 27, 2009

The newly disclosed scourge of ghost written clinical research publications should not only be banned prospectively, but retracted retroactively. The FDA bases its decisions as to safety, efficacy, and whether to grant an NME ("new molecular entity") expedited market approval under the Prescription Drug User Fee Act ("PDUFA"), in part, on clinical research publications. The FDA identifies "new risks" of marketed drugs and biologicals, on the basis of these articles and the AERS ("Adverse Event Reporting System"), and modifies the product's package labeling, accordingly. Most physicians base their clinical practice upon evidence found in these publications.

A Merck-funded study which appeared in the Annals of Internal Medicine in 2000, "Oral Montelukast Compared with Inhaled Salmeterol to Prevent Exercise-Induced Bronchoconstriction," Jonathan M. Edelman, et al. Ann Intern Med.2000; 132: 97-104 (http://www.annals.org/cgi/reprint/132/2/97.pdf), involving the Exercise Study Group, is a case in point.

Despite the two subjects who withdrew from the study because of worsening asthma, and the study subject that died after being exposed to salmeterol, the safety section of the publication states, "Both montelukast and salmeterol were well tolerated. Five patients were withdrawn from the study because of a clinical adverse event (four in the salmeterol group and one in the montelukast group). Of the patients who received salmeterol, one was withdrawn because of insomnia, two were withdrawn because of worsening asthma, and one died as a result of bronchial asthma. The investigator reported that this patient had mild persistent asthma and met all inclusion and exclusion criteria for the study. The death was classified as probably unrelated to study therapy. The patient who received montelukast was withdrawn because of exacerbation of asthma and allergic conjunctivitis."

Soon after publication of this pharma-funded and likely ghost written study, Eric P. Brestel, M.D. of Greenville, NC wrote a Letter to the Editor of the Annals of Internal Medicine to express his concerns about the Edelman, et al study comparing montelukast with salmeterol in the long-term treatment of exercise-induced bronchoconstriction. Brestel wrote, "First, why do such a study? Most people do not exercise more than once daily, and one or two inhalations of a short-acting beta-agonist is effective at a fraction of the cost of salmeterol and montelukast. My second concern is the requirement that anti-inflammatory medications (corticosteroids) be withdrawn. According to the authors, their patients met the criteria for moderate asthma; the recommendation of the National Heart, Lung, and Blood Institute is that such patients receive anti-inflammatory medication. Two patients withdrew from the study because of worsening asthma, and one died!" [(http://www.annals.org/cgi/reprint/133/5/392-a.pdf) in the Annals of Internal Medicine]

Dr. Brestel also wrote, "My last concern is that a journal that is held to high standards by its subscribers should print an article that raises such questionable ethical concerns, especially when the benefit from the knowledge gained from the study is negligible. When issues such as these get past institutional review boards, peer-reviewed publications are obligated to weigh the risks versus the benefits of medical research."

How many hospitalizations and deaths resulted from pharma-funded misinformation as to the safety of the long-acting beta agonists ("LABAs"), prior to FDA ordering black box warnings on the LABAs, citing increased risk of asthma-related death? How many hospitalizations and deaths will result while they remain in the marketplace? Drug labeling precautions for the leukotriene inhibitors, were requested of the manufacturers by FDA after a growing number of neuropsychiatric events were reported, which included suicide.

Given the serious ethical concerns voiced by Dr. Brestel and the recent article by Singer and Wilson of the New York Times, regarding the ghostwriting crackdown by medical editors, one really wonders what went wrong at the Annals of Internal Medicine to allow this particular study to not only be published, but to leave it unretracted. It is still widely cited today as if it was valid research. Let the ghost busting begin.

Robert Davidson, M.D., Ph.D.* is a practicing Internal Medicine physician for an outpatient clinic in Gladewater, TX.

*Disclosure: I have no current ties to the pharmaceutical industry. I am not an attorney. The views expressed herein are solely opinions and are in no way intended to represent legal or medical advice.