AstraZeneca's first chance to secure traditional approval for Iressa will be a randomized trial assessing symptom improvement in non-small cell lung cancer due to be submitted to the agency by June 2005.

The company will conduct "a randomized, controlled, double-blind, study comparing ZD1839 treatment with best supportive care in refractory, symptomatic stage III/IV NSCLC patients....Symptom improvement should be the primary endpoint of the study," FDA's May 5 approval letter for Iressa states.

FDA directed AstraZeneca to submit a protocol by June 13 with the goal of enrolling the first patient by November.

The agency granted accelerated approval to Iressa (gefitinib) "as monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel therapies."

The approval came after a review complicated by the failure of the drug to show a survival benefit in first-line trials and by postmarketing reports of adverse pulmonary events in Japan.

Although the review may not have been as uneventful as AstraZeneca would have wished, the company appears to have little to complain about in the final outcome: the Phase IV commitments appear to be achievable and the safety labeling is fairly clean.

Even the down-to-the-wire timing of the approval worked to the company's advantage. FDA appeared close to a final sign-off late on Friday, May 2 but ultimately held off until the user fee date, May 5. The mid-day Monday approval was more attractive from the point of view of capitalizing on the news cycle.

The user fee date was extended by three months to May 5 in order to allow FDA time to review postmarketing adverse event data from Japan (¹ Also see "Iressa User Fee Date Pushed To May; Will Advisory Cmte. Take Second Look?" - Pink Sheet, 13 January, 2003., p. 9).

The Japanese Ministry of Health began reporting cases of interstitial pneumonia associated with Iressa use in November. Japan approved gefitinib in July (² Also see "AstraZeneca Iressa NDA Review Complicated By Pneumonia Reports" - Pink Sheet, 4 November, 2002., p. 12).

FDA and the company agreed upon the least restrictive approach to the issue in final labeling: a warning statement under the heading "pulmonary toxicity." A stricter black box warning was understood to be under discussion very late in the review (³ Also see "Iressa Postmarketing Trial Modeled On Tarceva Phase III Under Consideration" - Pink Sheet, 5 May, 2003., p. 27).

"Cases of interstitial lung disease (ILD) have been observed in patients receiving Iressa at an overall incidence of about 1%," final labeling says.

"Approximately 1/3 of the cases have been fatal. The reported incidence of ILD was about 2% in the Japanese postmarketing experience, about 0.3% in approximately 23,000 patients treated with Iressa in a U.S. expanded access program and about 1% in the studies of first-line use in NSCLC (but with similar rates in both treatment and placebo groups)."

Labeling recommends that therapy be interrupted "in the event of acute onset or worsening of pulmonary symptoms" such as dyspnea, cough or fever. "A prompt investigation of these symptoms should occur. If interstitial lung disease is confirmed, Iressa should be discontinued and the patient treated appropriately."

The handling of the ILD issue in labeling appears to allow little room for managed care companies or other purchasers to restrict Iressa on safety grounds (see ⁴ Also see "AstraZeneca Prices Iressa At 25% Discount To Gleevec; Launch In May" - Pink Sheet, 12 May, 2003.).

The Iressa review had previously been slowed by the unexpected failure of AstraZeneca's Phase III INTACT trials. The studies could have served as confirmatory trials; the failure to show a survival benefit left FDA concerned about how to design an appropriate Phase IV program if it did grant accelerated approval.

FDA convened the Oncologic Drugs Advisory Committee in September to review the Iressa application after the trials failed. "If we didn't have these trials, we probably wouldn't even be here. We would have already approved the drug," Oncology Division Director Richard Pazdur, MD, told the committee (⁵ Also see "Iressa Cross-Over Study Could Show Clinical Benefit, AZ Says; ODAC Is Wary" - Pink Sheet, 30 September, 2002., p. 13).

FDA received the Phase II trials used for registration in December 2001. AstraZeneca did not complete the rolling NDA until Aug. 5, however, with the submission of the chemistry, manufacturing & controls section (⁶ Also see "AstraZeneca Iressa NDA Filing Complete: Will HIV Model Fly In Oncology?" - Pink Sheet, 12 August, 2002., p. 8). The negative Phase III results were released Aug. 19.

AstraZeneca delayed filing the CMC portion because it attempted to reformulate the pill to change the color from brown to yellow. The reformulation failed, however: "Iressa (gefitinib tablets) contain 250 mg of gefitinib and are available as brown film-coated tablets for daily oral administration," labeling states.

The pursuit of a cosmetic improvement to the tablets may have cost AstraZeneca a year on the market with Iressa. However, the delay meant that AstraZeneca avoided some difficult marketing challenges given the clinical trial failure and postmarketing safety reports.

The Iressa Phase IV program will serve as a test of Commissioner McClellan's emphasis on postmarketing surveillance as a way to allow faster approval of new drugs - and the willingness of industry to help in that goal. In an appearance at the Pharmaceutical Research & Manufacturers of America annual meeting, McClellan told industry that it is "time to take postmarket activities very seriously" (⁷ Also see "Rx Industry Must Take Phase IV “Seriously,” Commissioner Tells PhRMA" - Pink Sheet, 31 March, 2003., p. 3).

The Iressa approval was hailed in the business media as the latest sign that the FDA commissioner is having a salutary effect on the approval process; that may serve to increase the scrutiny of AstraZeneca's follow-through on the Phase IV side.

The symptom improvement trial is one of three Phase IV commitments that could form the basis of full approval for Iressa. It is the first due at FDA, and appears to be the most likely to satisfy the accelerated approval regulation requirements for demonstrating clinical benefit.

AstraZeneca sought a symptom improvement claim for Iressa in the original NDA based on the Phase II trials used for registration. Approximately 40% of Iressa patients reported improvement on the Lung Cancer Subscale of the Functional Assessment of Cancer Therapy, a much higher rate than the 10% tumor response rate seen in the trials.

FDA's Oncologic Drugs Advisory committee agreed that the tumor response rate was sufficient for an accelerated approval, but did not support the symptom improvement claim without data from a randomized, controlled trial (⁸ Also see "Iressa Symptom Improvement Claim Needs Controlled Study" - Pink Sheet, 30 September, 2002., p. 15). The ⁹ Iressa label follows that recommendation and does not include data on symptom improvement.

AstraZeneca's second postmarketing commitment is a randomized trial comparing survival of refractory lung cancer patients treated with Iressa plus best supportive care to patients receiving placebo plus supportive care. That trial is due to be submitted in October 2005. It is modeled on an ongoing study of Genentech/OSI's EGFR blocker Tarceva .

AstraZeneca will also conduct a trial comparing Iressa to Aventis' Taxotere (docetaxel), measuring survival and time to progression in non-small cell lung cancer. That trial is due by December 2006.

The FDA approval letter includes interim markers for each of the three trials, including protocol submission, start of enrollment and completion of enrollment. The level of detail is in keeping with the agency's recent expressions of concern about the pace of confirmatory trials for cancer drugs given accelerated approval (¹⁰ Also see "Accelerated Approval Needs Enforcement Mechanism For Confirmatory Trials" - Pink Sheet, 24 March, 2003., p. 30).

As a practical matter, the June 2005 submission date for the symptom improvement trial gives AstraZeneca two and a half years to establish Iressa in the marketplace before FDA would be in a position to consider whether it is showing clinical benefit.

With the last of the three full approval studies not due until the end of 2006, AstraZeneca is likely to have four years before the agency could reach any negative final conclusions about the product.

AstraZeneca has also agreed to complete two ongoing placebo-controlled survival trials in Phase IV, but not as a condition of accelerated approval. The first, which opened in October, will enroll a total of 1,160 patients with "completely resected Stage 1, 2 and 3A non-small cell lung cancer." The second, which has been open for a year, will study Iressa in 840 patients with inoperable stage III lung cancer pretreated with cisplatin/ etoposide/radiotherapy with consolidation docetaxel.

AstraZeneca's final Phase IV commitment reflects a different drug safety focus of the agency under McClellan: the company will "submit reports of all medication errors, both potential and actual, that occur within the U.S. with Iressa for two years following the date of approval."

The commitment is in keeping with FDA's proposed rule on medication errors issued in March (¹¹ Also see "FDA Medical Error Proposal Requires Reporting “Near-Misses” Within 15 Days" - Pink Sheet, 24 March, 2003., p. 26).

Iressa Clears FDA: Phase IV Symptom Trial Will Be First Shot At Full Approval

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