Erbitux Hearing Suggests Need To Revisit Fast Track Process – Rep. Burr

The Erbitux development problems suggest that the Fast Track process may not be working as well as expected, Rep. Richard Burr (R-N.C.) said during a June 13 Energy & Commerce/Oversight Subcommittee hearing on the ImClone/Bristol oncologic agent.

"We may need to go back and look at whether we need to change what we did" in creating the Fast Track process as part of the 1997 FDA Modernization Act, Burr said. The North Carolina Republican was one of the primary authors of FDAMA.

"We're where we were five years ago," Burr declared. "We're sitting in a committee hearing and we've got people pointing fingers at each other."

Energy & Commerce Committee Chairman Billy Tauzin (R-La.) also indicated interest in clarifying the Fast Track statute. "What I hope we will discern as we proceed through the investigation is how in fact the Fast Track process can be improved."

"I would hate for this hearing to somehow in any way cast aspersions upon what is an incredibly important process to make incredibly important drugs more quickly available to people," Tauzin added. "But at the same time, I expect we've got some real problems with the way the system works."

The Fast Track procedure codifies the portion of FDA's accelerated approval regulations that allows for approval based on surrogate endpoints, and authorizes sponsors who qualify to submit "rolling" applications.

The goal of FDAMA, Burr said, was to create a "clear roadmap at FDA" to "make sure that there is a process that not only the companies but the investors can have confidence in, that works." Congress "hoped to make that process a little more predictable and, we thought, a little more transparent." However, Burr declared, "we learn with every hearing that it is not quite as clear as we intended it to be. We as members of Congress have tremendous work left."

FDA and industry did not negotiate reforms on the scale of FDAMA as part of the Prescription Drug User Fee Act reauthorization in 2002.

However, the PDUFA III bill, signed into law the day before the hearing, includes a pilot program intended to build on the Fast Track process. FDA will develop a "continuous marketing application," where it responds to each portion of a rolling application within six months (¹ (Also see "PDUFA III Implementation Begins: FDA Working Groups Under Way" - Pink Sheet, 17 Jun, 2002.), p. 3).

The subcommittee's investigation of the Erbitux review process indicates that the complexities of applying Fast Track standards played an important role in the refuse-to-file letter for the Erbitux BLA. It also played a role in Bristol's decision to invest in Erbitux (see ² ).

Erbitux was granted Fast Track status on Jan. 12, 2001 based on a Phase II study (CP02-9923) which showed a 22.5% response rate in patients treated with cetuximab in combination with Pharmacia's Camptosar (irinotecan) in patients refractory to irinotecan.

However, a ³ subcommittee staff report says, FDA's decision to grant the Fast Track designation was based on ImClone's assertion that Erbitux does not show activity as a single agent.

"In the context that ImClone discussed this point," FDA assumed the data supporting the claim was derived from colorectal cancer patients, the report says. However, the claim was in fact based on a renal cancer study "which cannot be used as a basis for determining single-agent activity in colorectal cancer patients."

A week after granting the Fast Track designation, FDA informed the company that it would need to conduct a "small study of 25-50 patients to test the response rate when using Erbitux alone," the report notes.

"You must provide evidence that continuation of a toxic agent (irinotecan) is necessary to achieve the desired clinical effect" in order "for your development program to continue to meet the criteria for Fast Track designation," FDA said in the Jan. 19 letter.

As a whole, that clinical package requested by FDA put ImClone in the awkward position of "betting against their own drug to get the combination approval," Oncologic Drug Products Division Director Richard Pazdur, MD, told the committee.

Pazdur presented an extensive critique of the Erbitux development plan at the hearing, calling it "a very faulty design" (⁴ (Also see "Erbitux Oncologic Potential Endorsed By FDA, Bristol During House Hearing" - Pink Sheet, 17 Jun, 2002.), p. 7).

Energy & Commerce Committee Detailee Frank Papineau testified that there was another, more technical problem with the Fast Track designation: the agency's decision to grant Fast Track status was based on a misunderstanding of the 9923 protocol design.

According to the subcommittee report, ImClone amended the original August 1999 protocol design (which stated that enrollment is open to patients with "progressive disease during at least two cycles of standard doses of 5-fluorouracil and irinotecan") in October 1999 (to allow patients with "progressive disease at any time after receiving an irinotecan-containing regimen").

However, the report notes, the Fast Track designation specifies that it covers "refractory" patients, "where refractory is defined as progressive disease during at least two cycles of standard doses of 5-fluorouracil and irinotecan."

When questioned by committee members, ImClone CEO Harlan Waksal declared that he was unaware of the potential confusion about the change in protocols.

"At no time did we mislead FDA regarding what we were doing," Waksal said. "The fact that FDA didn't emphasize this issue even at the refusal-to-file time and the fact that I didn't recognize it until today, this doesn't seem to be a major issue regarding why we received a refusal-to-file."

Committee members did not question FDA witnesses during the hearing on the apparent confusion over the basis of the Fast Track designation.

However, the FDA witnesses did discuss their differences of opinion about whether Erbitux qualified for Fast Track status based on the 9923 study.

The primary medical reviewer of the application, Oncology Branch Medical Officer Susan Jerian, MD, felt that the agent would not be eligible for the designation. However, Division of Trial Design & Analysis Deputy Director Patricia Keegan, MD, overruled that judgment.

"I would attribute it to a difference of opinion in looking at the information," Keegan explained. "It was my assessment that a drug that purported to give an approximately 20% response rate in patients with refractory disease was something that should be evaluated further."

She noted that irinotecan was approved with a 13% response rate. "The setting was very similar" to the Erbitux review, she said.

However, the results ImClone submitted Oct. 12, 2001 from the single-agent study showed a 10.5% response rate. While the figure is well below the 22.5% rate reported in the combination trial, "the confidence intervals overlapped, and thus there was still a possibility that a very sick colorectal cancer patient could respond just as well with Erbitux alone as with Erbitux combined with a toxic chemotherapy," the staff report says.

In the refuse-to-file letter, FDA told the company that "the data do not show that the response rate observed with the combination of cetuximab and irinotecan could not also be observed with single-agent cetuximab at the dose and schedule proposed."

The failure of ImClone to resolve the single-agent activity of Erbitux was not the only issue in the refuse-to-file letter. FDA also believed that protocol violations and other record-keeping issues in the trial made it impossible to verify the response rates claimed by ImClone (see ⁵ (Also see "Clinical Trial Oversight May Be Ongoing Theme After Erbitux Hearing" - Pink Sheet, 24 Jun, 2002.)).

Waksal acknowledged "there were problems with the protocol," but added that "what's critical is that this study was not designed as a registration trial. It was a Phase II study, early on in the development of this drug. It was only because of the unexpected results that we were able to go ahead."

Rep. Bart Stupak (D-Mich.) pressed Waksal on the quality of the data in the 9923 trial and suggested that the protocol was inadequate to be considered for Fast Track status.

The exchange highlighted the cloudiness that surrounds the Fast Track standard. "It's still only a Phase II study," Stupak said. "You're asking for accelerated, Fast Track approval for the general population. You are past Phase II."

"Actually, it was Congress who stipulated in Fast Track legislation that studies exactly like this could be designated to be moved forward towards approval. Phase II studies, sir," Waksal said.

"Congress also said that if you're going to do Fast Track, it has to be tightly controlled, tightly regulated, and you must follow the regimen to a tee, otherwise, we're not going to allow it," Stupak replied.