When it comes to testing Merck’s (MRK) arthritis drugs, the biggest side effect for investors may be uncertainty.
Analysts, cardiologists and medical journals have criticized the studies of Vioxx, which is no longer sold, and Arcoxia, a new Merck product the Food and Drug Administration is expected to decide on next year.
The arguments over testing can make it difficult for those outside the company to assess a drug’s safety, even if the medication achieves its clinical goal.
The debate resumed last week after Merck said Arcoxia had the same cardiovascular risks as an older pain reliever, diclofenac, according to studies involving more than 30,000 arthritis patients. Diclofenac is a nonsteroidal anti-inflammatory drug, or NSAID, the same class that includes naproxen and ibuprofen.
Arcoxia is a COX-2 inhibitor, the same type of drug as Vioxx and Pfizer’s (PFE) Celebrex. Arcoxia is available in 62 foreign markets, but Celebrex is the only COX-2 drug in the U.S.
On the Offensive
The carping about Arcoxia actually began several months before Merck released the results of the study known as MEDAL. Critics say Merck shouldn’t have used diclofenac, arguing that it has a higher cardiovascular risk than naproxen.
Negative comments came from the Journal of the American Medical Association, which printed an editorial from Dr. David Graham in September. Graham is the FDA researcher who gained attention for criticizing Vioxx, Merck and the FDA review process at a Senate hearing two years ago.
Writing as a private citizen, Graham said Merck was “stacking the deck” by using diclofenac and by designing a test in which Arcoxia simply had to be shown as no worse than the older drug.
Merck defended its methodology as “a well accepted design for comparing safety or efficacy of two treatment groups.” Merck said it used diclofenac because it is the world’s most-prescribed NSAID.
The company also said the test results were consistent with an April 2005 FDA memo that contends long-term clinical trials “have not shown a difference in cardiovascular safety between selective COX-2 inhibitors and nonselective NSAIDs, with naproxen as a possible exception.”
However, some analysts say Arcoxia may have trouble getting past the FDA. Physicians consulted by SG Cowen say that “if a placebo-controlled study is conducted, the result would likely not favor Arcoxia.” Merck says it didn’t compare Arcoxia with a placebo, because giving patients a sugar pill in a long-term study of arthritis would have been unethical.
Cowen warned in a recent research report that the FDA might require Merck to do another study comparing Arcoxia and naproxen. On the basis of the latest tests, “we believe it is doubtful that Arcoxia will be approved,” says Cowen, which is neutral on Merck.
One or more Cowen analysts tracking Merck or members of their households own shares. Cowen seeks to do or does business with companies covered in research reports.
“We think public pressure will prevent the FDA from approving Arcoxia without studies better demonstrating its safety,” Sagient Research Systems, which analyzes drug-research prospects, says. Sagient doesn’t own shares and doesn’t have an investment-banking relationship.
Sagient says evidence has grown that diclofenac has a “relatively high risk” for cardiovascular problems. One study, recently printed in JAMA, found that diclofenac had a slightly higher heart risk than Vioxx, depending on the dose. Another study says diclofenac’s heart risk was greater than that of naproxen.
Importantly, Sagient notes that these studies are meta-analyses—in other words, a combination of many tests to examine themes that might not be apparent from a single test. “While such analyses are not as definitive as large clinical trials,” Sagient says, diclofenac “might not have been the best comparator to demonstrate safety for Arcoxia.”
Merck has said that the meta-analyses and Graham’s commentary “are not supported by the current weight of clinical trial data.”
Room for Discussion
The Arcoxia issue illustrates the difficulty in reaching consensus about what a particular study means, but it isn’t first time such a debate has emerged.
Naproxen played a big role in a bitterly contested Vioxx study published in the prestigious New England Journal of Medicine in November 2000. The study, called VIGOR, measured gastrointestinal side effects between Vioxx and naproxen—an important consideration for people taking pain relievers, especially the elderly. Vioxx patients had fewer problems.
In March that same year, preliminary data from the VIGOR trial revealed that Vioxx patients had a higher risk of cardiovascular problems. Merck scientists suspected that the difference was due to the benefits of naproxen rather than the dangers of Vioxx.
Still, a warning was added to Vioxx’s label. Critics, however, said the change was insufficient, and a recent JAMA article said naproxen didn’t exhibit heart-protecting properties.
In late 2005, after Vioxx was off the market, the NEJM told the VIGOR authors to correct their original article. The journal said three heart-attack cases among Vioxx patients weren’t included in the article. Merck said the data were detected too late to meet the publication’s deadline and said it promptly reported the information to the FDA and the scientific community.
The journal’s top editors assailed the study’s design, and they resumed their criticism in February this year. Merck officials and outside researchers said they wouldn’t make a correction because they followed proper protocol in designing and reporting the results.
VIGOR wasn’t the only source of friction between Merck and the journal, which published another Vioxx study in March 2005 and later ripped Merck’s methodology and interpretation. This was the APPROVE study, which led Merck to withdraw Vioxx in September 2004. The company is now being sued by thousands of former users of the drug.
APPROVE examined whether Vioxx could reduce colon polyps, thus providing a defense against colon cancer. Merck compared Vioxx to a placebo.
The APPROVE study says cardiovascular risk occurred only after patients took Vioxx for more than 18 months. Otherwise, Merck said there was no statistically significant difference between Vioxx and placebo. Critics attacked Merck’s interpretation.
In June 2006, the New England Journal of Medicine published a correction to the APPROVE article, saying the 18-month claim should be removed from the original. The article’s conclusion of no difference between Vioxx and a placebo prior to 18 months should also be deleted, the journal’s editors said.
Saying that the correction “centered on the description of a single statistical method,” Merck maintains that Vioxx’s cardiovascular risk emerges only after 18 months.