FDA’s Next Accelerated Approval Process: “Targeted Cancer Drugs”

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Sunday, April 12 2009

FDA’s Next Accelerated Approval Process: “Targeted Cancer Drugs”

By Cole Werble

Two former FDA Commissioners are working on development of new regulatory pathway for approval of oncologics rooted in the principles of accelerated approval.

Former FDA Commissioners David Kessler and Mark McClellan are urging the agency to develop a new process for accelerated cancer drug approval to take advantage of biomarker identification of specific patient populations and drug activity.

Kessler has been talking publicly about a new approval process for cancer drugs for over a year (The RPM Report, March 2008). He raised the issue as the centerpiece of an address to the Pharmaceutical Research and Manufacturers of America annual meeting in San Antonio on April 4.

“We need to identify the most significant opportunities and develop pathways to improve the rapid availability of more effective, targeted cancer therapies – and outline specific steps in the development and regulatory process for acceleration of targeted cancer development while continuing to assure safety and effectiveness,” Kessler declared.

In his view, one of the highlights of his six-plus years at the top of FDA was the agency’s aggressive participation in helping to define an accelerated approval pathway for HIV therapeutics.

He still likes to recount the joint work by the National Institute of Allergy and Infectious Diseases and FDA reviewers to speed the assessment of raw clinical trial data generated by companies developing the first protease inhibitors and to use that information to develop a foreshortened route to approval.

Using the data from companies and analyzed by FDA and NIH scientists, FDA “set out a roadmap and industry followed it to a T,” Kessler said.

FDA should again step in proactively into the development process for cancer drugs, Kessler believes. “We need to create such roadmaps, a next generation of accelerated approval. We’ll see what it ends up looking like but one that possibly could be called something like ‘targeted approvals.’”

Noting that McClellan, FDA commissioner from late 2002 to early 2004 and now the head of the Engelberg Institute at Brookings, has “been doing a lot of thinking on this.” Kessler said that the new process “should be based on pre-specified markers, both positive and negative.”

A targeted cancer approval process would include five basic elements, Kessler said.

1) It would be designated for a specific cancer or stage of disease that does not have an existing standard therapy.

2) Biomarkers would have to be identified to judge patient response in disease models.

3) Studies would be conducted on biomarker positive or biomarker-enriched positive populations to show clinical benefit.

4) Steps would be in place to provide reimbursement for patients who are biomarker positive.

5) FDA approval would be conditioned on post-marketing studies to test broader populations and to confirm clinical benefit.

“Obviously,” he said, “there needs to be a lot of work on the details.” For example, concepts such as “clinical benefit” would need more precise definitions.

Kessler sees a clear opening for a change in approval criteria: either from the new leadership at FDA under Commissioner-designate Margaret (“Peggy”) Hamburg or Deputy Commissioner Josh Sharfstein or from congressional activity to revamp the effort against cancer.

Kessler suggests that he will have access to the new FDA topside team and that they will be receptive to taking an active role on cancer approvals. Not many FDA commissioners seek out the advice of their predecessors. Kessler, however, believes his previous experience with Hamburg and Sharfstein may make this team different.

Kessler also has ties to a former Obama health transition team member, Greg Simon, the head of Faster Cures, who is actively lobbying to get Kessler a position in the health establishment, perhaps at NIH. If Simon is successful in helping Kessler find a place in the administration, that could increase his access to the FDA management team.

Kessler left the position of dean of the University of California San Francisco medical school in late 2007. He is still affiliated with the medical school.

“I know and have worked with each one over the last decade,” Kessler observed. “Josh was my intern; Peggy and I worked together when she was commissioner of health in New York City and there were not drugs for tuberculosis readily available.”

Sharfstein worked at FDA in the Office of the Commissioner while in medical school. He worked on the addiction analysis that was central to Kessler’s argument for FDA to have more control over tobacco. Kessler describes Sharfstein’s contributions as brilliant.

If personal connections and his previous FDA experience do not get attention at FDA, Kessler can ride increased pressure on FDA from Congress to the same purpose.

Congress Pushing For Cancer Changes Also

A Senate bill, S. 717, introduced on March 26 by the Sens. Ted Kennedy, D-Mass., and Kay Bailey Hutchinson, R-Texas, calls for changes in FDA’s efforts to help develop cancer biomarkers and use them in the approval process. The bill’s discussion of biomarker development suggests that an accelerated approval as described by Kessler would fit right in with the intended objectives of the proposed legislation. (“The Pink Sheet”, April 6).

The bill, for example, calls for a combined FDA, Centers for Medicare and Medicaid Services and National Cancer Institute effort to “develop guidelines for the conduct of clinical studies designed to generate clinical data relating to cancer care and treatment biomarkers that is adequate for review by each Federal agency.”

The bill would also state the “Sense of the Senate” that FDA would place high priority on the use of biomarkers to establish effective strategies for selecting patients for treatment with specific drugs.

The legislation is expected to go to markup in the Senate HELP committee, chaired by Kennedy, in late April. In the House, Lois Capps, D-Calif., is taking the lead on corresponding legislation. Capps is vice chair of the Energy and Commerce Committee’s Health Subcommittee.

Kessler is keeping up with activity on the Capitol Hill and told PhRMA that he had been visiting Congress prior to his speech to the association. He further noted that President Obama’s aggressive statements on cancer research further help the climate for adoption of new approval processes.

One of the major hurdles weighing against an innovative effort to overhaul part of the cancer approval process will be simply the number of competing priorities facing Hamburg and Sharfstein. Food safety will clearly take up management time. Kessler, who started his tenure at FDA taking on food labeling claims, noted that food safety “has emerged on the Hill and in the public mind along with health reform as one of the defining issues” in the health arena.

“Peggy and Josh understand that their legacy will be determined in many ways by how well they handle food safety,” Kessler observed. He noted that the intense attention to food safety brings with it the debate over whether to split the agency into two separate regulatory entities – which will further hinder the management team’s ability to deal with issues like the cancer drug approval process.

Kessler tried to put food safety and cancer therapies into a broader perspective. “If we want to have an impact on public health, moves on food safety are important – but there are, what, 5,000 deaths a year from food-borne pathogens.”

That is “certainly too many” deaths from food safety problems, “but,” Kessler noted, the effect of cancer is more widespread and threatening: “one in two men and one in three women will develop one form of cancer in their lifetimes.”

The public health backgrounds of Hamburg and Sharfstein should lead them to keep an “eye on where is the path of greatest impact in people’s lives.” Kessler also noted that FDA will be under close scrutiny from Congress to deal with medical device approvals (and the aging 510(k) device approval process and the more fundamental issue of whether drug and device sponsors are providing accurate and honest data to the agency.

Kessler believes that naming a pair of FDA top managers simultaneously is a good move. “The administration deserves a lot of credit” for coming up with the solution, Kessler said.

The two-person team offers the agency the “priceless gift [of] the possibility of stability of leadership for the next four years if not the next eight years.” Kessler’s own tenure of six-plus years is the longest that the agency has had since the 1950’s. When he left, the agency had an interim commissioner for almost two years. The new team has “the potential for succession built in.” Kessler said Hamburg and Sharfstein are a team “that potentially can be in place for a significant period of time,” Kessler declared.