FDA's announcement of an ongoing safety investiation regarding a possible increased risk of cardiac events with AstraZeneca's Prilosec (omeprazole) and Nexium (esomeprazole) is the first test case of the agency's new policy of releasing emerging drug safety information.

The "Early Communication About an Ongoing Safety Review" for the two proton pump inhibitors, released August 9, is the first such communication since FDA released its final guidance on communication of drug safety information to the public in March.

The final guidance eliminated the proposed "Drug Watch" Web site to track emerging safety issues - which drew intense criticism - but still provides for public dissemination of that information (¹ Also see "FDA To Continue Providing Emerging Safety Info, But Not Through Drug Watch" - Pink Sheet, 2 April, 2007., p. 25).

FDA had released similar announcements prior to the new policy, with a disclaimer about the preliminary, unvetted nature of the safety signal. The Prilosec/ Nexium announcement carries a similar statement (as called for in the guidance) that "Posting this informaion does not mean that FDA has concluded there is a causal relationship between the drug products and the emerging safety issue. ... FDA is considering, but has not reached a conclusion about whether this information warrants any regulatory action."

At a same-day press conference to discuss the "Early Communication" on Prilosec and Nexium, FDA officials commented on their new strategy on informing health care providers and the public about emerging safety issues that impact public health.

"It is an evolution in our thinking as to when we should be communicating information as we are receiving the results of clinical trials and at what point in our review and analysis we should be communicating information to the public," CDER Associate Director for Safety Policy and Communiation Paul Seligman said.

Seligman said that the Early Communication differs from previous public health advisories in that safety information will be released earlier in the evaluation process before the review is completed.

He did make some cautionary statements about the potential ramifications of releasing unverified safety concerns. "We are always aware and concerned about the potential consequences of our announcements," Seligman stated. "That's why we are very explicit in this statement that prescribers as well as patients should not change their prescribing patterns or use patterns based on the fact that we received some initial information and are conducting an analysis."

Based on the data released and FDA's comments on Prilosec and Nexium thus far, the situation appears to be a function of the agency's intention to be more proactive and transparent about post-market drug safety than a reflection of the level of the agency's concern about the data.

The safety signal was detected in two small, long-term studies in patients with severe gastrointestinal esophageal reflux disease, in which patients were randomly assigned to receive treatment with either Prilosec or Nexium or to undergo surgery.

The data began filtering into FDA on May 29, when AstraZeneca submitted the completed study involving Prilosec and the other ongoing trial with Nexium. Through July, FDA continued to receive data from AstraZeneca from the two studies as well as pooled analyses of other controlled clinical studies, including placebo-controlled trials of up to two years' duration.

FDA officials declined to reveal the number of patients enrolled in the trials or the number of specific cardiac incidents that were reported.

In the completed 14-year Prilosec study, "more patients treated with omeprazole had heart attacks, heart failure and heart-related sudden death than did the patients who had surgery," FDA said. The difference was seen in the first year and continued over time.

According to AstraZeneca, although the non-blinded omeprazole study showed "an apparent difference" in cardiac event reporting rates, "a separate evaluation of other controlled clinical trials of 12-24 months' duration, involving omeprazole and placebo in approximately 2,900 patients, shows a lower cardiac event reporting rate amongst omeprazole-treated patients than for placebo-treated patients."

Five-year follow-up information was available from the study with Nexium, which is still ongoing. "While the initial data from this study suggested a difference between treatments in the rate of cardiovascular events, an updated report submitted by AstraZeneca found that the number of patients who experienced heart problems was similar in both treatment groups," FDA noted.

In the early communication, FDA points out that the study protocols did not specify how heart problems were to be defined or documented, making the evaluation difficult. Further, the agency notes that many of the patients randomized to surgery did not complete the surgery, and that those who did receive the surgery were younger and had less history of heart problems or risk factors - which "could have biased and significantly influenced the safety data."

FDA concluded that the data does not suggest an increased risk of heart problems for patients treated with either drug and recommended that health care providers and patients should not change either their prescribing practices or their use of the products.

In response to FDA's Early Communication, AstraZeneca issued a statement that also stated "the study results conclude that the products are not associated with an increased risk of cardiac events and do not change the overall benefit/risk profile of omeprazole and Nexium."

The agency reported that its preliminary conclusion about the two studies is further supported by an additional analysis of 14 comparative studies of Prilosec, of which four were placebo-controlled. In these studies, patients were treated for up to two years and there were fewer heart attacks or other cardiac problems in Prilosec patients compared to patients who were administered placebo.

"Although these studies were not specifically conducted to assess the risk of heart problems, and patient follow-up is incomplete, they do not suggest an increased risk of heart problems with the use of omeprazole," FDA said.

Seligman added that the FDA has not determined whether a more comprehensive review of the PPI class is appropriate until the current review is completed. He did comment that the ongoing safety review does not apply to the lower-dose, over-the-counter version of Prilosec, which is marketed by Procter & Gamble.

When questioned during the press briefing why FDA did not make an announcement closer to AstraZeneca's first submission at the end of May, Seligman responded that "we were concerned about the initial results and missing information," and that the additional data coming in was "less alarming."

"Part of this process is that it is somewhat of a moving target for us in that we are accumulating more information as we are conducting our analysis," he noted.

FDA expects to complete its review within three months and at that time communicate its conclusions and recommendations to the public.

- Anthony Vecchione (a.vecchione@elsevier.com)

Prilosec/Nexium Alert Is Debut Of FDA’s Early Communication Of Safety Issues

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