The Saga of Study 3014 and the Safety of Telithromycin

An article in the Wall Street Journal by Anna Wilde Matthews (subscription not required to access article) raises questions about the integrity of the clinical research evidence about the antibiotic telithromyci (Ketek) made by Sanofi-Aventis.

Background

Telithromycin is a ketolide, a molecular modification of erythromycin with some similarity to macrolide antibiotics. In the US, it is approved by the Food and Drug Administration (FDA) for treatment of outpatient upper respiratory infections and pneumonia.

A brisk review of the drug is found in this editorial in the Annals of Internal Medicine: Turner M, Corey GR, Abrutyn E. Telithromycin. Ann Intern Med, Mar 2006; 144: 447 - 448. This editorial notes concerns about the liver toxicity of the drug, based in part on a case report of three patients in the same issue ( Clay KD , Hanson JS, Pope SD, et al. Severe Hepatotoxicity of Telithromycin: Three Case Reports and Literature Review. Ann Intern Med, Mar 2006; 144: 415 - 420.). One patient required a liver transplant, and one died. The case report also noted that Sanofi-Aventis reported seven cases of hepatitis or hepatocellular damage in patients taking telithromycin in data from Phase III trials. Also, the FDA received ten post-marketing surveillance reports of serious liver problems in patients taking the antibiotic, and often, other drugs.

The Wall Street Journal Article

The article focused on a large randomized controlled trial, study 3014, initiated by Aventis (to become Sanofi-Aventis) in 2001. According to the WSJ article, "Aventis first sought permission to sell Ketek in the U.S. in March 2000. Fifteen months later the FDA refused to approve it." So, "Aventis originally undertook study 3014 in 2001 at the request of the FDA, which was worried about liver damage, blurry vision and other possible side effects from Ketek after reviewing the company's earlier trials." Then, "Aventis hired a contractor called Pharmaceutical Product Development Inc. (PPD), which specializes in coordinating clinical trials." The study was designed to enroll patients with respiratory infection seen in the offices of 1824 primary care physicians. Patients were randomized to telithromycin or amoxicillin/clavulanate potassium (Augmentin).

Problems were soon discovered at study sites that enrolled the most patients.

• The study eventually enrolled 407 patients from the office of Dr Maria "Anne" Kirkman Campbell. Her practice "attracted patients by advertising weight-control treatments." By January, 2002 she was enrolling "30 new people a day." Minutes from a PPD study management meeting stated that someone was a "little uncomfortable" with the site, which required "additional monitoring." In February, 2002, Nadine Grethe, "an Aventis manager overseeing the study," got an email from PPD warning of problems at the site with lack of "proper diagnosis of an appropriate medical condition" for study patients, and that medical charts were "very limited," and laboratory test results "suspiciously similar." A statistical analysis by Aventis failed to indicate problems with the data. "When Aventis turned in the results of study 3014 to the FDA on July 24, 2002, they included 407 patients from Dr. Campbell. At this point, 'Aventis did not alert the Agency to any problems....'" Yet when an FDA inspector examined Dr Campbell's office in the fall of 2002, chosen simply because of the volume of patients enrolled there, problems found included "patients [who] said they hadn't gotten any medication," patients "who were allegedly being treated fro weight loss, and not respiratory infections," and some who "were family members and friends of Dr. Campbell." Later, "Sanofi-Aventis says it was only after the government investigation that it discovered Dr. Campbell was fabricating data." Dr. Campbell eventually plead "guilty of one count of mail fraud in March, 2004 and was sentenced to four years and nine months in federal prision."
• The site with the third greatest number of patients, 214, was that od Dr. Egisto Salerno. His "medical license was on probation during the study." "Aventis told the FDA in December 2002 that it didn't know Dr. Salerno was on probation." An FDA inspection found "use of white-out on some study documents." Seven weeks after ending study enrollment, "police found Dr. Salerno with cocaine in his underwear and a loaded handgun," and he eventually surrendered his medical license, and plead guilty to a misdemeanor, which was later expunged after community service and drug counseling.

However, "when a committee of outside adviers to the FDA met early in 2003 to weigh a recommendation on Ketek, agency officials didn't mention the problems turned up by its inspections. The FDA's Dr. [Janice] Soreth and Dr. Jenkins say revealing the suspicions might have biased the decision and impaired the investigation. The committee voted to recommend Ketek's approval. Two weeks later the FDA rejected the recommendations. It asked Aventis for more documents on study 3014 and potential side effects overseas. Aventis complied. But the FDA ultimately decided the study was so flawed that the data couldn't be trusted." After considerable internal debate, "the FDA formally approved Ketek on April 1, 2004...." "FDA officials said they believed the original Aventis data submitted in 2000, plus the data from smaller studies and the drug's safety record oversea, justified approval."

The WSJ article noted that study 3014 was cited in an "article in the New England Journal that suggested Ketek is as safe as other antibiotics. Five of the six authors of that article disclosed that they received consulting fees from Sanofi-Aventis, and the sixth was an Aventis employee at the time of the study." The article mentioned in the WSJ appears to be this report of a randomized controlled trial of talithromycin versus placebo for patients with acute asthma ( Johnston SL, Blasi F, Black PN, Martin RJ, Farrell DJ, Nieman RB, the TELICAST Investigators. The Effect of Telithromycin in Acute Exacerbations of Asthma. N Engl J Med 2006; 354:1589-1600.) In apparent reference to safety information derived from study 3014, Johnston et al concluded, "among patients with normal liver aminotransferase levels at entry, the incidence of elevations of at least three times the upper limit of normal after treatment was similar among patients receiving telithromycin and drugs used for comparison."

The WSJ quoted US Senator Charles Grassley (R-Iowa, and Chair of the Senate Finance Committee), "the Ketek allegations appear to be as serious as anything I've seen so far." Additionally, US Representatives Edward Markey (D-Massachusetts), and Henry Waxman (D-California) are separately investigating. Rep. Waxman said he is "deeply disturbed," and that Aventis "failed to disclose to FDA grave flaws in a key safety study."

Summary

At best, this appears to be yet another story about a drug trial that was poorly executed by a contract research organization, and not rigorously supervised by a pharmaceutical company. We have previously discussed apparently sloppy work by other contract research organizations (see post here). Furthermore, results from this poorly executed trial seem to have been used to suggest that telithromycin is relatively safe, even though the integrity of the data provided by this trial is questionable.

The story of study 3014 appears to be yet another cautionary tale about how the clinical evidence that physicians and patients rely upon to make clinical decisions must be regarded with skepticism. Our skepticism about particular research studies needs to be extended not just to the usual considerations of study design, the nature of the data collected, and the appropriateness of the statistical analysis. We must now be skeptical about the details of the study execution, particularly when the study has been done by a contract research organization, and worry about problems that may go beyond just honest mistakes.