Greater availability of clinical trial data through online databases could lead to more independent reviews of study results akin to a published analysis of Pargluva data, Bristol-Myers Squibb U.S. Pharmaceuticals President Anthony Hooper speculated during a press meeting Nov. 18.

"There is going to be a constant debate" over clinical outcomes, the exec said. He called such discussions "healthy" and predicted they could become even more robust in the future.

Bristol executives addressed third-party analysis of clinical trial results in relation to the company's investigational type 2 diabetes drug candidate Pargluva (muraglitazar).

An independent data analysis published online in the Journal of the American Medical Association Oct. 20 found a higher incidence of death and cardiovascular events with the drug than in the data analysis presented to FDA by the company.

An accompanying editorial by James Brophy (McGill University) called for delaying approval of Pargluva.

The JAMA analysis was based on publicly available data submitted by Bristol to FDA's Endocrine & Metabolic Drugs Advisory Committee for its review of Pargluva.

Bristol, like many pharmaceutical manufacturers, has recently updated its policies on making clinical trial information available to the public. The company's policy calls for disclosing the results of any Bristol sponsored trial of a marketed medicine regardless of phase or outcome.

Bristol posts results on the Pharmaceutical Research & Manufacturers of America clinicalstudyresults.org website.

"Probably the industry has been a bit slow in the case of making clinical data available to the public," Worldwide Pharmaceuticals President Lamberto Andreotti said.

Although Pargluva was deemed "approvable" by FDA and received a positive advisory committee recommendation, following the JAMA publication Bristol announced that additional clinical trials assessing cardiovascular risk and requiring up to five years to complete would be required to gain regulatory approval for the therapy.

The news prompted Merck, Bristol's co-development partner, to drop out of the partnership, while Bristol said it would continue to evaluate whether or not to move ahead with development of the dual peroxisome proliferator-activator receptor agonist (¹ Also see "Pargluva Panic: Need For Additional Trial Prompts Merck To Drop Partnership" - Pink Sheet, 31 October, 2005., p. 3).

When asked if FDA was influenced by the JAMA article, Andreotti responded, "I do not think the FDA was influenced at all by the article. That is my personal opinion."

Hooper said the company has submitted a response to JAMA addressing statements in Brophy's editorial. Brophy maintained that the application for Pargluva included methodological decisions that "foster an illusion of safety" that are "perhaps unintended but nevertheless disingenuous."

"I think that editorial was disingenuous," Andreotti stated. "It did not reflect the good work that we have done on Pargluva."

Brophy also cosigned a Nov. 17 letter from Public Citizen to FDA that urged the agency to reject the Pargluva application.

"We were convinced when we submitted the filing, and are still convinced, that it's an important product," Andreotti said.

"We are still looking at the product, we are still talking with the FDA, we are still discussing with opinion leaders what needs to be done to answer the questions that the FDA has."

He said Bristol would not reach a decision on whether or not to proceed with additional Pargluva trials before the end of the year.

"The exercise of looking at Pargluva and the new circumstances is still going on, and the only conclusion we have reached is that this is not a short-term opportunity for us," he said.

However, even if Pargluva were to be approved, marketing a diabetes drug with a cardiovascular risk profile could prove challenging because diabetics are already at risk for cardiovascular problems.

Hooper said that under such circumstances, Bristol would likely pursue marketing of Pargluva on a case-by-case basis for patients failing their current treatment and facing serious consequences, including organ failure.

"I wouldn't label the product as a product with a completely wrong CV profile," Andreotti added. "Otherwise, we wouldn't be looking at it still."

The exec emphasized that risk is inherent in drug development, particularly for therapies in new drug classes.

"If you want to deliver innovation, you must be innovative, and you must go where others have not been, and it's more risky," Andreotti said.

"At the same time, it is 2005. The environment is not becoming easier, the post- Vioxx environment in the U.S. and elsewhere doesn't make the approval of products easier," he added.

In October, Pfizer CEO Hank McKinnell suggested that his company's R&D initiatives had been negatively impacted by the risk-averse environment at FDA following the withdrawal of Merck's Vioxx from the market last year (² Also see "Pfizer Parecoxib, Oporia Setbacks Reflect Tougher FDA Stance, CEO Says" - Pink Sheet, 24 October, 2005., p. 17).

McKinnell said that two of the drugs in Pfizer's development pipeline - the COX-2 inhibitor parecoxib and the osteoporosis prevention agent Oporia (lasofoxifene) - would not have received "not approvable" letters had the decisions come two years earlier, prior to the Vioxx withdrawal.

Bristol's Andreotti, however, noted that while "it is clear that Vioxx has created some different ways of thinking" at FDA, it is not possible to know if Pargluva would have been approved two years ago.

"We still find...the dialogue with the FDA, very constructive, so we are not fighting with FDA over Pargluva," he said.

Pargluva Effect: Bristol Foresees More Independent Scrutiny Of Trial Data

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