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Gleevec^TM for the Treatment of Chronic Myelogenous Leukemia: U.S. Food and Drug Administration Regulatory Mechanisms, Accelerated Approval, and Orphan Drug Status

Division of Oncology Drug Products (HFD-150), Center for Drug Evaluation and Research and Office of Orphan Products Development, Office of the Commissioner, Food and Drug Administration, Rockville, Maryland, USA

Correspondence: Martin H. Cohen, M.D., Food and Drug Administration, HFD-150, 5600 Fishers Lane, Rockville, Maryland 20857, USA. Telephone: 301-594-2473; Fax: 301-594-0499; e-mail: cohenm{at}cder.fda.gov

	ABSTRACT

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Gleevec^TM (imatinib mesylate), a highly promising new drug for the treatment of chronic myelogenous leukemia in blast crisis, in accelerated phase, and in chronic phase after interferon failure or intolerance, received orphan drug status from the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development on January 31, 2001, and accelerated approval from the FDA for the above three indications on May 10, 2001. The purpose of this report is to summarize FDA regulatory mechanisms, i.e., accelerated approval and orphan drug regulations, that have permitted patients to receive this drug as rapidly as possible.

Key Words. Gleevec • Imatinib mesylate • Chronic myelogenous leukemia • Food and Drug Administration • Accelerated approval regulations • Orphan drug regulations

	INTRODUCTION

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Gleevec^TM (imatinib mesylate capsules, Novartis Pharmaceuticals), a drug that targets bcr-abl tyrosine kinase, the putative cause of Philadelphia chromosome-positive chronic myelogenous leukemia (CML), received accelerated Food and Drug Administration (FDA) approval on May 10, 2001. Approval was for treatment of CML in blast crisis, CML in accelerated phase, and CML in chronic phase after failure of interferon treatment. All approvals were based on results of nonrandomized, single-arm trials (see below). The two-and-a-half month review time makes imatinib mesylate the fastest FDA-approved cancer drug ever.

The regulatory highlights of imatinib mesylate development are indicated in Table 1. The time from first patient enrollment to new drug application submission was 32 months, less than half the usual time for trials to be completed, analyzed, and submitted for review. This was especially remarkable since CML is an uncommon disease (approximately 4,500 Americans are diagnosed each year). Despite that fact, 1,027 patients were recruited by 10 participating institutions (four U.S. and six European).

The most recent prevalence data for CML indicate fewer than 50,000 patients in the U.S. As a treatment for CML, imatinib mesylate qualified for designation as an orphan product under the 1983 U.S. Orphan Drug Act. Designation as an orphan, i.e., achieving "orphan status" in the U.S., is based upon the use of the product to treat or diagnose a rare disease or condition with a patient population under 200,000. The U.S. Orphan Drug Act amended the Food, Drug, and Cosmetic Act, and established incentives for the pharmaceutical industry to develop drugs that otherwise have limited commercial value and, consequently, little industry support. The incentives of the Orphan Drug Act are administered by the FDA Office of Orphan Products.

Among the provisions included in the orphan drug legislation are 7 years of exclusive marketing for sponsors of drugs and biological products which have a product designated as an orphan that is approved by the FDA for that indication. In addition to market exclusivity, orphan designation provides tax credits for clinical research costs during development, grant support for the investigation of rare disease treatments, and a waiver of FDA prescription drug user fees initiated by the 1992 Prescription Drug User Fee Act. As of May 19, 2001, FDA had approved 220 orphan products for market.

The U.S. Orphan Drug Act did not change the legal requirements for investigating drug products to be used in treating rare diseases in the U.S. Like all drugs, orphan-designated products must be proven safe and effective before FDA will approve them for marketing. They undergo the same FDA review process as a non-orphan product. Most orphan products are developed to treat life-threatening diseases for which no other drugs are available, and may therefore receive priority status within the FDA review process. Nevertheless, the parameters for approving a drug to treat the disease are not compromised.

The surrogate end points supporting imatinib mesylate efficacy were hematologic and cytogenetic response rates (response rate is the classic surrogate end point for oncology trials). Eighty-eight percent of 532 chronic-phase, interferon-failure CML patients had a confirmed complete hematologic response (two consecutive determinations separated by at least 4 weeks), and 49% had a confirmed (two consecutive determinations separated by at least 4 weeks) or unconfirmed (single determination) major cytogenetic response (a major cytogenetic response combines both complete [0% Philadelphia chromosome-positive (Ph⁺) metaphases] and partial [1%-35% Ph⁺ metaphases]. Patients have not been followed for a sufficient length of time to estimate response durations or survival. Hematologic response (complete = no evidence of leukemia or return to chronic phase) was observed in 63% of 235 accelerated-phase patients and in 26% of 260 blast-crisis patients. Major cytogenetic response was observed in 21% of accelerated-phase and 13.5% of blast-crisis CML patients. Similar to chronic phase CML patients, it is too early to estimate response durations and survival for accelerated-phase or blast-crisis patients.

Important adverse effects associated with imatinib mesylate treatment included fluid retention, gastrointestinal irritation, hematologic toxicity, and hepatotoxicity. Mild to moderate peripheral edema occurred in the majority of patients in all three studies. Severe fluid retention (pleural effusion, pericardial effusion, pulmonary edema, ascites) occurred in 1%-2% of patients. The probability of developing fluid retention was greater at higher imatinib mesylate doses and with age >65 years. Because of gastrointestinal irritation associated with imatinib mesylate, patients are advised to take the drug with food and a large glass of water. Because imatinib mesylate treatment is associated with neutropenia and thrombocytopenia, complete blood counts must be performed at appropriate intervals. Severe elevations of transaminases and/or bilirubin occurred in 1.1%-3.5% of patients and were usually managed by dose reduction or interruption. Hepatic toxicity required permanent discontinuation of therapy in 0.5% of patients. However, one patient who was taking acetaminophen regularly for fever died of acute liver failure (see discussion of phase 4 commitments).

Because follow-up of most patients treated with imatinib mesylate is relatively short and because patients will likely be taking this drug for years, additional observation is required to completely document serious side effects.

Applicant phase 4 commitments required for accelerated approval include: provision of interval follow-up information on the three trials that provided a basis for accelerated approval, and completion and submission of the final study report for a randomized trial comparing imatinib mesylate to interferon- combined with cytarabine in patients with newly diagnosed, previously untreated, Ph⁺ CML in chronic phase. Time to progression (TTP) is the primary end point of that trial. TTP is defined as any of the following: loss of complete hematologic response, loss of cytogenetic response, inability to maintain peripheral blood counts, increasing organomegaly, occurrence of accelerated-phase or blast-crisis CML, or death from CML.

The applicant’s commitments, which are not a condition of the accelerated approval, include: A) completion of an ongoing dose-finding study in children with refractory/ relapsed Ph⁺ leukemias and initiation of appropriate pediatric efficacy studies; B) conduct of a hepatotoxic drug interaction (e.g., acetaminophen) study; C) conduct of an imatinib mesylate pharmacokinetic study in subjects or patients with liver impairment; D) conduct of an in vitro study to assess the plasma protein binding of the therapeutically active N-demethylated piperazine derivative of imatinib mesylate; E) evaluation of the etiology and treatment of the imatinib mesylate fluid retention syndrome, and F) implementation of a physician and patient education program regarding the use of concomitant medications with imatinib mesylate.

Imatinib mesylate is metabolized predominantly by CYP3A4 and to a lesser extent by CYP2D6. CYP3A4 inducers or inhibitors can be expected to decrease (inducers) or increase (inhibitors) imatinib mesylate blood levels. Whether CYP2A6 inducers or inhibitors act comparably requires further study.

	CONCLUSIONS

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Rapid approval of imatinib mesylate was a combined effort of the FDA and Novartis Pharmaceuticals. Both efforts were motivated by the desire to provide Ph⁺ CML patients with an additional, effective, therapeutic option as rapidly as possible.

	ACKNOWLEDGMENT

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The views expressed are independent work and do not necessarily represent the views and findings of the U.S. FDA.

Received April 30, 2002; accepted for publication July 9, 2002.

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