Merck still believes that the initial cardiovascular safety signal seen for Vioxx can be explained by a cardioprotective effect from naproxen, the company said during an Oct. 13 press conference in New York City.

"We still believe that there is plausibility to the naproxen hypothesis given what we knew about naproxen before and also given the data that has come forward since that time, which continues to show a decreased incidence of events," VP-Clinical Research Alise Reicin, MD, said.

Reicin pointed to Novartis' recently reported TARGET trial, which found a numerical difference in the rate of cardiovascular events seen with the experimental COX-2 inhibitor Prexige compared to naproxen (¹ Also see "Prexige TARGET Study: Not Quite A Bull’s-Eye For Novartis" - Pink Sheet, 23 August, 2004., p. 20).

Merck held the press conference to talk about its clinical development work on Vioxx (rofecoxib) and the timeline that led to the decision to withdraw the COX-2 inhibitor Sept. 30 (² Also see "Merck After Vioxx: No Merger, But No Big Near-Term Launches" - Pink Sheet, 4 October, 2004., p. 3).

In particular, Merck responded to allegations that it downplayed the increased cardiovascular event rate seen in the VIGOR trial.

A Public Defense

The study, completed in 2000, compared Vioxx to the older nonsteroidal anti-inflammatory drug naproxen with the intent of showing a gastrointestinal safety advantage. However, the study found an increased rate of cardiovascular adverse events in the Vioxx group.

Merck argued at the time that the result reflected a cardioprotective benefit of naproxen. After an FDA advisory committee review and an extensive period of negotiations, Vioxx labeling was changed in April 2002 to include the VIGOR results (³ Also see "Vioxx Label Balances CV Risk With GI Safety: Can Merck Reverse Damage?" - Pink Sheet, 15 April, 2002., p. 20).

The decision to withdraw Vioxx came after the firm found an increased risk in cardiovascular events for colon polyp patients treated with the drug compared to those receiving placebo in the APPROVe trial.

Merck's theory about the cardioprotective effect of naproxen has been challenged in the medical literature since the VIGOR data were first presented, and the company's handling of the finding forms an obvious line of attack for plaintiffs' attorneys pursuing cases related to the withdrawal of the drug.

One particular challenge for the Merck will be explaining a September 2001 warning letter from FDA objecting to its description of the VIGOR study and the naproxen hypothesis (⁴ Also see "Vioxx Withdrawal Fuels Criticism Of DTC; Liability Exposure May Be Test" - Pink Sheet, 11 October, 2004., p. 4).

FDA Warning Letter Put In Context

Merck General Counsel Kenneth Frazier declared that "it is important to understand exactly what that letter dealt with."

"It addressed three separate promotional activities," including "a specific set of speaker programs, a press release and then statements made by representatives at two medical meetings."

"It did not state that the agency believes Vioxx caused those cardiovascular events," Frazier said. "Second, it does not require or suggest that the prescribing information for Vioxx should be changed."

"We addressed those specific speaker programs and the two medical meetings cited in that letter by FDA by sending communications to health care professionals who were exposed to them," Frazier said. "FDA did not require Merck to take action with regard to the press release...and FDA considered the matter closed."

The company declared during the press briefing that it still believes the VIGOR data reflect the virtues of naproxen, not the risks of Vioxx.

Faith In Naproxen

Reicin acknowledged that it is "impossible to say one way or the other" whether "you could completely at this point in time rule out any effect of Vioxx" on the safety signal in the VIGOR trial.

However, she declared, "what we saw in VIGOR was very different than what we saw in APPROVe."

"In VIGOR, we saw separation of the event rates on Vioxx and naproxen almost from the beginning of the study," and the full data covered a mean treatment time of nine months.

"Whereas, in APPROVe, the event rates didn't start to separate until after 18 months of continuous use."

Reicin was asked why Merck did not attempt to develop additional data about the cardioprotective effects of naproxen to support its theory.

"We did do some additional testing to look at naproxen, to look at in a kind of pro-thrombotic experimental model whether naproxen would act like aspirin, and in fact it did," she replied.

However, "the most important question for us was to make sure that Vioxx, in fact, didn't have a cardiovascular risk."

Merck Research Labs President Peter Kim noted that the APPROVe study was under way before the VIGOR data came out, but that Merck added a cardiovascular safety endpoint to the trial as part of its efforts to assess the risk of Vioxx. The company also added cardiovascular safety endpoints to post-marketing studies of Vioxx in other indications.

Observations On Observational Studies

Merck did not conduct a long-term placebo controlled trial of Vioxx in pain indications because of the difficulties of enrolling such a trial, Kim said.

In the ongoing investigations of Vioxx, Merck and FDA will also be asked to defend their response to a second study that suggested an increased cardiovascular risk: an observational study using HMO claims data (⁵ Also see "COX-2 Retrospective Study Prompts Review By FDA, Kaiser On Merck’s Vioxx" - Pink Sheet, 30 August, 2004., p. 6).

Reicin argued that it would be inappropriate to base regulatory decisions on that type of study. "There are inherent limitations of observational studies," she declared.

"I think they are hypothesis-generating. They can lead to further research...but you have to take the results of those studies in the context of clinical trials."

Reicin cited Wyeth's experience with the conjugated estrogens franchise and the Women's Health Initiative trial as an example.

"Hormone replacement therapy is the best example of how observational studies have led us astray," she declared. "A decade of observational studies with hormone replacement therapies - study after study after study - suggested that hormone replacement therapy was cardioprotective."

"And yet, when the randomized clinical trial was done, it was the opposite that was found."

She pointed out that two other NSAIDS - indomethacin and naproxen - "were also found to increase the risk of heart attacks" in the claims study.

Arcoxia Update

From a regulatory standpoint, Merck's most immediate challenge is to manage the ongoing FDA review of the follow-on COX-2 inhibitor Arcoxia (etoricoxib) while working with international regulators in the 47 countries that have already approved the drug.

Arcoxia is pending at FDA with a user fee deadline at the end of October. Merck is still not speculating about the likely outcome of that review in light of the Vioxx withdrawal, but Kim did talk more specifically about the company's plans for the brand in markets where it is already approved.

"We are working in regulatory agencies" in the countries where Arcoxia is marketed "to come up with appropriate prescribing information that would reflect how the APPROVe study results should be taken into account as one uses Arcoxia," he said.

"We are working with regulatory agencies and have provided the APPROVe results to those agencies," Kim noted. "In addition...on Oct. 8, we provided to key European regulatory agencies a safety update on Arcoxia."

"At this point in time, it would be speculative to try to say whether the results of APPROVe have any bearing on the profile of other COX-2 inhibitors or NSAIDs," Kim added. Merck noted that the only products in the class with publicly available long-term safety data are Vioxx and aspirin.

No "Short Term" Risk

"I will also add that there are substantial data which indicates that for short-term use, there is not a cardiovascular risk with Arcoxia," Kim said.

Merck will be presenting 12 month data comparing Arcoxia's cardiovascular safety to diclofenac during the upcoming American College of Rheumatology conference. The data show no difference in cardiovascular events between the two agents.

The company is also scheduled to present the APPROVe data during the meeting on Oct. 18.

Merck’s “VIGORous” Defense Of Vioxx; Novartis, Wyeth Studies Might Help

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