Researchers Apologize for Disclosure Failure on Drug Study

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athritisHealthDay News -- The failure of researchers to fully disclose pharmaceutical-industry connections in a study of drugs used to treat rheumatoid arthritis has resulted in a letter of apology to the Journal of the American Medical Association.

However, everyone involved is quick to note that both the findings of the study and the methods used were sound. And while the exact meaning of the findings is the subject of debate, there appears to be no question of the validity of the science involved.

The original study appeared in the May 17, 2005, issue of JAMA. In that study, Dr. Eric L. Matteson, a professor of medicine at the Mayo Clinic, and colleagues looked at the risk of cancer among patients taking infliximab (Remicade, Enbrel) and adalimumab (Humira) for rheumatoid arthritis.

These drugs are tumor necrosis factor-alpha blockers (TNFs). TNF blockers bind to tumor necrosis factor-alpha, making it inactive, reducing inflammation and joint damage.

These drugs have been associated with an increased risk of some cancers, particularly lymphoma, and with an increased risk of infection.

In its study, Matteson's team concluded: "There is evidence of an increased risk of serious infections and a dose-dependent increased risk of malignancies in patients with rheumatoid arthritis treated with anti-TNF antibody therapy. The formal meta-analysis with pooled sparse adverse events data from randomized controlled trials serves as a tool to assess harmful drug effects."

The disclosure problem arose because the researchers failed to tell JAMA editors that they had let Abbott Laboratories, the maker of Humira, review the paper before it was published because they had a prior agreement to do so. However, they did not let Centocor Inc., the maker of Remicade, review the paper, since they had no such agreement with that company. They also failed to note that a TNF drug made by Wyeth was not included in the study, even though they were working with Wyeth on another study.

In addition, the Mayo researchers didn't tell the journal they had received $25,000 from Amgen, the marketer of Enbrel, for the fellowship education training of Dr. Tim Bongartz, one of the study co-authors. "The stipend was not linked to the study or systematic review of TNF-alpha antibodies," Drs. Bongartz and Matteson write in the apology letter.

"This was really a very embarrassing thing to me," Matteson said. "This occurred due to my inattention to our disclosure statement when we submitted our original paper. There were mistakes in the disclosure, not because I intended to mislead them, but simply because I was negligent."

According to Matteson, he alerted JAMA editors to the error a week before the study was to be published -- a fact disputed by Dr. Catherine D. DeAngelis, JAMA's editor-in-chief, who said she was first notified by one of the drug companies involved.

"It was very nice of him [Matteson] to do it after the fact, since he knew we were about to initiate an investigation because someone let the cat out of the bag," DeAngelis said. "We are very serious about it. I don't like it when people don't fully disclose. I wanted this letter of apology."

Based on DeAngelis's concern, the Mayo Clinic looked into the matter and instituted conflict-of interest-education for its researchers.

The disclosure issue did not stop JAMA from publishing the study on schedule. Both Matteson and DeAngelis agree there was nothing wrong with the science in the paper.

"No one is questioning the veracity of the paper," DeAngelis said. "What we are questioning is why they didn't disclose."

Based on this and other occurrences surrounding disclosure, JAMA tightened its disclosure policy on conflicts of interest.

In a July 12, 2006, JAMA editorial, DeAngelis announced an updated disclosure policy. "To further improve the transparency of reporting of potential conflicts of interest and to encourage more accurate and complete disclosures, an important new policy is that JAMA will begin requiring all authors to disclose all potential conflicts of interest in the 'Acknowledgment' section of the manuscript at the time of submission," she wrote.

Despite the disclosure problems, Matteson stands behind the findings in the study. Basically, the study found that there is a significant risk of developing cancer associated with these drugs. However, in terms of actual cases, the risk is small, he said.

"The cancer events are relatively rare," Matteson said. "But the relative risk is increased. Whether that holds up in other studies isn't known. We also documented that there was an increased risk of infection. That remains a concern with these drugs."

"The real bottom line is that these are very effective drugs for the treatment of rheumatoid arthritis, and are with justification used in patients with severe disease," Matteson said. "However, they do interfere with immunological function. We have to be concerned that in individual cases this interference may cause adverse events."

Patients need to be told about the risk, so they can make an informed decision whether to use them or not, Matteson said.

Several letters in this week's JAMA devoted to Matteson's study find fault with the methodology used or the findings. But all agree there are risks with the drugs to one degree or another. In fact, the risk of cancer and infection are stated on the drugs' labels.

One expert has problems with the methods used in the study.

"There are a lot of problems with meta-analysis [a review of previous studies]," said Dr. Elinor Mody, a rheumatologist at Brigham and Woman's Hospital, in Boston. The inclusion in the Matteson study of certain skin cancers and cancers that develop over a long time are particularly concerning, she noted. In addition, the study authors didn't include data on the drugs from other important trials.

However, Mody tells her patients that with rheumatoid arthritis, there is an increased risk of lymphoma. "Maybe these medications increase the risk even more," she said. "The concern about infection is nothing new -- and that's my major concern," she said.

"We are not at the point that these drugs are first-line agents," Mody said. "But this study didn't really change my mind about these medications. For some patients, they are wonder drugs."

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