BioWorld Insight Contributing Writer

Earlier this month, the European Committee for Medicinal Products for Human Use (CHMP) issued a positive recommendation for InterMune Inc.'s idiopathic pulmonary fibrosis (IPF) drug Esbriet (pirfenidone). The European Medicines Agency (EMA) is expected to ratify the decision in a few months, clearing the way for InterMune to launch the drug in Europe. (See BioWorld Today, Dec. 20, 2010.)

The FDA wasn't as convinced about Esbriet's efficacy. Despite a positive recommendation by the FDA's Pulmonary-Allergy Drugs Advisory Committee, the agency issued a complete response letter in May asking for data from another clinical trial. (See BioWorld Today, March 10, 2010, and May 5, 2010.)

The dichotomy isn't unusual. There are plenty of examples of regulators from separate countries coming to different conclusions about the same drug.

In 2008, Merck & Co. Inc.'s cholesterol drug Cordaptive (MK-0524) was approved by the EMA, but Merck said the FDA required additional efficacy and safety data before it would allow the drug on the market. Merck will have to wait until the results of HPS2-THRIVE are available in 2013 before resubmitting to the FDA.

Bristol-Myers Squibb Co. had the reverse experience. Its breast cancer drug Ixempra (ixabepilone) was approved by the FDA in 2007, but the CHMP was concerned that the "very small increase in survival" didn't outweigh the potential damage to nerve cells. In March 2009, BMS withdrew its application for marketing authorization of Ixempra in the EU.

Different Modes of Operation

The biggest difference between the FDA and EMA review processes is that the FDA uses outside experts for its advisory panels, while the EMA's CHMP is made up of regulators from each of the 27 member states. The FDA therefore sometimes comes to a different conclusion than its independent advisors, but the EMA almost always ratifies the decisions of the regulators comprising its CHMP.

In fact, InterMune chairman, president and CEO Dan Welch told BioWorld Insight that their research only found one instance where the EMA didn't ratify a CHMP decision – and that was only because of new data that came to light after the CHMP's review. CHMP originally gave Janssen-Cilag International N.V.'s antibiotic Zeftera (ceftobiprole) a positive recommendation, but when the FDA's review discovered that "studies had not been conducted in compliance with good clinical practice in some [clinical trial] sites," the EMA didn't come on board. CHMP later revised its stance and recommend against approving Zeftera, and the EMA ratified the second recommendation.

The FDA and EMA's different modes of operation explain how the committees' recommendations can have different effects on the regulators' final outcomes, but that doesn't explain how the two agencies can ultimately come up with different decisions when presented with the same supporting materials.

"The information in the packets [submitted to each agency], for all practical purposes, wasn't different," Welch told BioWorld Insight. "During the review process, the Europeans brought up the same issues that the FDA did," he added.

Those issues included the fact that one of InterMune's two Phase III trials of Esbriet did not meet its endpoint, although the pooled data showed a clinically meaningful benefit in reducing the decline in lung function in IPF patients. Concerns had also been raised about one potential case of drug-related liver injury and serious adverse gastrointestinal and skin events.

But in the end, "the Europeans, in terms of a universally fatal disease, determined that the benefits outweighed the risk," Welch said. He isn't sure why the FDA came to a different conclusion.

John Graham, director of health care studies at the Pacific Research Institute, is more cynical about discrepancies between the agencies' decisions. "If the reviews were scientific truth, you should see less variation between the outcomes. There must be some bureaucratic differences rather than a scientific one," he said.

Transparency and Competition

A detailed explanation of why the agencies made their decisions might shed some light on the issue. CHMP publishes a short summary of its opinion whether positive or negative, and FDA advisory committee meetings are open to the press, but the FDA doesn't give any public explanation about its decision when it issues a complete response letter.

Publication of the complete response letter would be helpful to investors, but Welch pointed out it would also be beneficial to the company's competition. "I'm all for transparencies, but not where it compromises company's interests," he said.

In a report penned earlier this year, Graham proposed a different approach to clearing up differences between FDA and EMA decisions. He suggested that the FDA should allow drugs to be marketed in the U.S. if they've been approved by the EMA. It's a radical idea, but he feels patients should have access to drugs available in other countries . . . and he thinks a little competition between regulatory agencies could help speed up the drug approval process.

When the EMA was originally established, companies were allowed to apply to each country individually or directly to the EMA, which, "created competition for user fees among those regulatory agencies," Graham wrote.

According to Graham's research, during a 12-month period from May 2008 through April 2009, there were 13 drugs that were eventually approved by both the FDA and EMA. The EMA approved those drugs 97 days earlier, on average. Additionally, there were 11 drugs that were approved by the EMA during that period, but which hadn't received FDA approval by the end of the reporting period.

While Graham's idea is unlikely to come to fruition, he pointed out that competition for user fees would certainly get the FDA's attention, since those fees now account for more than half of the FDA's budget.