AstraZeneca Refocuses Risk Management, Elevates Development Oversight

AstraZeneca's product development and regulatory affairs overhaul will include a review of ongoing Phase III programs for Galida , Cerovive and Symbicort .

"We will be including a review of Cerovive, of Galida and of Symbicort U.S. programs," CEO Tom McKillop said Dec. 17 during an analyst call.

Galida (tesaglitazar) is a dual peroxisome proliferator-activated receptor agonist in development for the treatment of type 2 diabetes. Cerovive (NXY-059) is being developed for treatment of acute ischemic stroke. Both are new molecular entities.

Symbicort, in development for asthma and chronic obstructive pulmonary disorder, is a combination of AstraZeneca's Pulmicort (budesonide) and formoterol, the active ingredient in Schering-Plough's Foradil .

[Editor's note: Coverage of an FDA ad division letter citing Foradil promotions appeared in ¹ "The Pink Sheet" DAILY Dec. 27. To read the article and sign up for a free trial, visit our website, www.ThePinkSheetDAILY.com.]

Review of AstraZeneca's Phase III programs will be one of the responsibilities of former Exec VP-Product Strategy & Licensing John Patterson, who has been promoted to the board-level position of exec director-development effective Jan. 1.

The move to place responsibility for product development under a board-level position is part of AstraZeneca's broader refocusing of its clinical and regulatory activities following development hurdles for two significant products: the anticoagulant Exanta and the oncologic Iressa .

"AstraZeneca is committed to the development of innovative medicines, but Exanta and Iressa, two products based on breakthrough science, have suffered setbacks," McKillop said.

AstraZeneca announced the same day that a confirmatory Phase III trial evaluating Iressa (gefitinib) failed to show a survival benefit in patients with lung cancer (see ² (Also see "AstraZeneca To Revisit Iressa Dosing Following Failed Survival Study" - Pink Sheet, 3 Jan, 2005.) ). Iressa was approved in May 2003 based on a surrogate endpoint.

Exanta (ximelagatran) received a "not approvable" letter in October following a negative review by FDA's Cardiovascular & Renal Drugs Advisory Committee (³ (Also see "AstraZeneca Rethinking Blockbuster Model After Exanta “Not Approvable”" - Pink Sheet, 18 Oct, 2004.), p. 27).

"Following the non-approval of Exanta by FDA, we accelerated a significant program of change in the development and regulatory functions, based on the learning from these and other experiences," McKillop said. Patterson's board-level appointment "is a further step in this process."

In his new role, Patterson will oversee "the design and implementation of all clinical and regulatory programs with emphasis on rigorous risk management and risk assessment," the CEO said.

Patterson will also assume responsibility for the "implementation of substantial changes to the clinical organization and its processes" and the "improvement of our regulatory capability and our effectiveness in interactions with regulatory authorities," he said.

Prior to its elevation to a board-level position, drug development oversight was split between Exec-VP Global Drug Development Martin Nicklasson and VP-Discovery Research Jan Lundberg.

As part of the management changes, Nicklasson will replace Patterson as exec VP-product strategy & licensing.

"The kind of company that AstraZeneca is is, I think, a very innovative one. We put an enormous importance on innovation and creativity," McKillop said.

"I am not sure that we have put the same weight on challenge, to use that word," McKillop said. "I am not sure that we have been really taking apart the clinical programs from the point of view of 'where are all the risks?' and 'have we really optimized the risk management of the whole program as well as we might?'"

"Coupled with that is this whole question of our interaction with the regulatory authorities," the CEO said. "We get a lot of feedback from the regulatory authorities along the lines of they like dealing with us. I mean, it sounds perverse, but we are nice guys."

AstraZeneca needs to determine if the company is "actually asking ourselves and asking the regulatory authorities the difficult questions. Are we really addressing and sharing those kinds of questions with the regulatory authorities early enough?"

Although McKillop's remarks focused on Exanta and Iressa, one of the most significant challenges currently facing AstraZeneca relates to safety questions surrounding Crestor (rosuvastatin).

The cholesterol-lowering agent is one of the drugs at the center of a broader debate over FDA's postmarketing surveillance system following the withdrawal of Merck's Vioxx (⁴ (Also see "Crestor, Serevent Safety Issues Push Vioxx Out Of Spotlight In Senate Hearing" - Pink Sheet, 22 Nov, 2004.), p. 4).

Crestor has also been a flashpoint for debate over direct-to-consumer advertising.

FDA issued an "untitled" letter Dec. 21 citing a Crestor DTC print ad for minimizing the risk of the 40 mg dose of rosuvastatin and for misrepresenting the agency's position on the drug's safety (see ⁵ (Also see "AstraZeneca Crestor Defense Minimizes Risk Of High Dose, FDA Says" - Pink Sheet, 3 Jan, 2005.) ).

AstraZeneca ran the ad several days after FDA Office of Drug Safety Associate Director for Science David Graham identified Crestor as one of five drugs with unresolved safety issues during a Nov. 18 congressional hearing on Vioxx (⁶ (Also see "AstraZeneca Crestor Ad Defends Safety, Re-Asserts Superiority Claims" - Pink Sheet, 29 Nov, 2004.), p. 10).

McKillop has acknowledged the potential for drug companies' marketing efforts to undermine R&D. The CEO recently said manufacturers' promotional spend is roughly double that for R&D, noting that those figures make it hard to "use the R&D argument successfully" (⁷ (Also see "Rx Marketing Spend Does Exceed R&D, AstraZeneca CEO Says" - Pink Sheet, 22 Nov, 2004.), p. 23).

Those remarks came shortly after FDA Acting Commissioner Lester Crawford cautioned against running DTC ads that make comparative claims (⁸ (Also see "FDA Talking Tough On DTC: Is Viagra Letter First Of Many?" - Pink Sheet, 22 Nov, 2004.), p. 12).

A TV ad for Crestor describes the product as "clearly the best" when compared to other statins in a head-to-head study.

AstraZeneca appears to have recently reduced the number of national ad buys for Crestor. The company said it has not halted the rosuvastatin campaign.