FDA and EMEA: Minding the Gap

“EMEA is not the FDA of Europe, and the FDA is not the EMEA of the United States.”

That’s how Richard Pazdur – the head of FDA’s Office of Oncology Drug Products – started off a panel on oncology regulatory initiatives at ASCO on May 30. “We recognize that there are different laws, different interpretations of existing laws and different cultural issues that can be brought into play in making regulatory decisions,” he added.

But with consistency, and transparency, in mind, the two regulatory bodies do practice openness. FDA’s entire oncology review team has monthly teleconferences with key EMEA officials. They go over pending regulatory actions, recent meetings with sponsors, proposed regulatory initiatives and even occasional staff exchanges (a regulate-abroad program?).

There is also a free exchange of documents – minutes from end of Phase II meetings, important regulatory letters. “Really the oncology program with this interchange has been one of the models that the FDA and the EMEA want to emulate in other therapeutic areas,” Pazdur said.

Still, Pazdur, who received a personal plaudit for his stewardship of cancer drug approval process with a career recognition award, kept honing in on the differences between the European regulatory system and the FDA process. The way Pazdur referenced some of those differences could constitute a wish list for additional authorities the FDAer would like to have.

One key difference is in the enforcement mechanisms for early approval of innovative therapies – accelerated approval in the US, and conditional approval in Europe. Pazdur deems these functionally equivalent: “it’s a matter of terminologies.”

“But there are differences here. Both of the programs have options to take the drug off the market if clinical benefit or subsequent trials are not done,” Pazdur pointed out. With its longer experience with accelerated approval (EMEA only adopted conditional approvals last year), there have been more tests in the US. And even when a drug has failed in its mandatory trial to confirm the benefit that was the basis of the accelerated approval (AstraZeneca’s lung cancer therapy Iressa), FDA opted not to outright rescind the marketing authorization, instead laying on marketing restrictions and limiting distribution. Still, “most of our drugs have not faced that issue of coming off the market,” Pazdur admitted.

The US legislation on accelerated approval stipulates that sponsors should approach confirmatory trials with “due diligence” – which, Pazdur added, “really is in the eyes of the beholder. Let’s face it, it does not have a legal definition. Whereas I noticed the Europeans were a bit more clever and probably learned from our experience. They put a one-year review, and we don’t have that.”

The EMEA’s Francesco Pignatti made clear that they don’t really have the explicit authority to rescind the approval for compliance reasons, though the one-year re-review remains untested. “It’s only in the case of adverse new information that one could see this change,” he predicted. But the opportunity to reconsider the emerging knowledge of a drug’s risk-benefit was clearly an aspect Pazdur admires.

The FDA official expressed some frustration with the way sponsors handle confirmatory trials for accelerated approval. “Several ODAC meetings have discussed the sometimes lack of due diligence on the part of sponsors in fulfilling these commitments,” Pazdur pointed out. “They are mandatory commitments and should be taken quite seriously by the sponsor.”

There too the EMEA built in a mechanism that FDA would find useful: the European regulators can impose financial penalties if the postmarketing studies are not delivered as agreed.

Consultation with external experts is one area where Pazdur seems to prefer the US system, though he handled the comparison with diplomacy. Unlike the FDA advisory committee system, the EMEA’s Scientific Advisory Group meetings are closed to the public. They’re even mostly closed to the companies involved (there are open portions of the meeting for the sponsor to make a presentation, but then the discussion is closed off again). Pazdur questioned whether the process would be improved or hindered by having public involvement.

Without any experience with that, Pignatti declined to speculate, although he did note the EMEA is “rather far” from having public access for those meetings. Pazdur, however, jumped in – having attended both SAG and CHMP meetings “and obviously the ODAC meetings.”

“To be honest there’s a remarkable similarity as far of the discussions,” he said. In fact, the consistency – reassuringly – holds up with the internal regulatory processes as well, he noted. “Although we’re independent agencies and usually have not discussed the applications prior to our teleconferences, many of the exact same issues come up. And although people love to point to the differences between decisions that the EMEA and the FDA make, by far there’s more similarities than any differences.”

Despite the “lack of transparency” Pazdur noted in the European system for external consultations, the FDAer openly admired the transparency that EMEA gives regarding negative regulatory decisions. The EMEA publishes its negative opinions and reviews on withdrawn applications as well as the positive opinions. “One of the issues that we have in the FDA, which is quite problematic for those of us that work in the FDA,” Pazdur noted, is that when the agency does not approve a drug, the review documents and even the complete response letter that lays out the deficiencies in that application are not released to the public. Companies could release that information (although trust us, they don’t), but FDA is tied from even commenting.

“So this I think is one of the main reasons that we have this apparent lack of transparency, because we cannot release negative information. When we approve a drug, all that information goes out on the web. But for non-approvals, it’s truly the black box warning, so to speak, in its ultimate form,” Pazdur said. --Mary Jo Laffler