Affiliations of authors: Division of Oncology Drug Products (RD, JJ, GW, RP), Division of Therapeutic Biological Oncology Products (PK), Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, MD
Correspondence to: Ramzi Dagher, MD, HFD-150, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 1451 Rockville Pike, Rockville, MD 20852 (e-mail: dagherr{at}cder.fda.gov)
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ABSTRACT |
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INTRODUCTION AND REGULATORY HISTORY |
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In 1992, Accelerated Approval Subpart H was added to the new drug application regulations. This addition allows accelerated approval of drugs for serious or life-threatening diseases if the drug appears to provide a benefit over available therapy; the benefit is determined by the drug's effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on evidence of an effect on a clinical benefit other than survival. Drugs granted accelerated approval for which uncertainty exists as to the relation between the surrogate endpoint and clinical benefit or between the observed benefit and ultimate outcome must be studied further by the applicant to verify and describe the drug's benefit. The FDA expects that confirmatory studies to demonstrate that treatment with the drug is associated with clinical benefit will usually be underway at the time of accelerated approval, though that is not a specific requirement. If confirmatory studies are not performed with due diligence or do not demonstrate clinical benefit, the Code of Federal Regulations describes a mechanism for removing the drug from the market (2).
In general, the FDA has considered an effect on survival or relief of patient symptoms as evidence of clinical benefit in oncology. Objective tumor response rates and time-to-progression have often been viewed as surrogate endpoints that are reasonably likely to predict clinical benefit. Objective response rates and/or time-to-progression have been accepted as evidence of clinical benefit in some circumstancesfor example, when relatively nontoxic products are evaluated, such as hormonal therapies for breast cancer and some biologic products. Durable complete responses have been accepted as evidence of clinical benefit in hematologic malignancies when response has been associated with an established clinical benefit parameter, such as improved survival, reduced rate of infection, or reduced need for transfusion (35). These endpoints have also been accepted for other malignancies, such as testicular cancer, because the response was of sufficient magnitude and duration that it appeared to be associated with improved survival.
In March 1996, "Reinventing the Regulation of Cancer Drugs," a document from the office of the President of the United States (6), described the application of the accelerated approval regulations by the FDA to new cancer treatments. Specifically, the document stated that accelerated approval of oncologic drugs would be based on the demonstration of tumor size reduction in patients with refractory disease or in patients whose disease had no effective therapy (6). The document also addressed post-approval confirmatory studies as follows: For products approved on the basis of tumor shrinkage, post-approval studies will usually be required to further define the utility of the new drug, either alone or in combination with other agents, for the approved and/or other indications. For accelerated approval of drugs that ameliorate treatment-associated toxicities, post-approval studies will be required, as appropriate, to examine the effect of the therapy on survival and/or to demonstrate that the surrogate measures correspond to clinical benefit. A post-approval study will not necessarily be required in the exact population for which approval was granted. For a product that was approved to treat patients with a refractory malignancy, additional information from that population may not, for example, be as useful as randomized controlled studies in a previously untreated population.
Trial design and the populations enrolled in clinical trials for drugs submitted for accelerated approval, as well as the status of confirmatory studies for selected accelerated approvals, were discussed at an Oncologic Drugs Advisory Committee meeting held March 1213, 2003, in Bethesda, MD. This review summarizes the FDA experience with the accelerated approval process for oncology drugs and discusses trial design, patient population selection, and the integration of accelerated approval into a comprehensive drug development plan.
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SUMMARY OF ACCELERATED APPROVALS FOR ONCOLOGY PRODUCTS UNDER SUBPART H |
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Of the six oncology drugs initially granted accelerated approval and subsequently converted to regular approval, two drugs (docetaxel and irinotecan) were initially studied in comparative studies, and four drugs (capecitabine, dexrazoxane, imatinib mesylate, and oxaliplatin) were studied without an active comparator.
In 1996, docetaxel (Taxotere) was approved for second-line treatment of breast cancer. Approval was granted on the basis of objective response rates evaluated in six U.S. and three Japanese single-arm studies (7). The six U.S. studies enrolled a total of 309 women, of whom 190 had anthracycline-resistant disease. The overall objective response rate for these 190 women was 37.9% (95% confidence interval [CI] = 31.0% to 44.8%). The three Japanese studies enrolled a total of 174 evaluable patients. The overall objective response rate in 26 women, whose best response to an anthracycline had been progression, was 34.6% (95% CI = 17.2% to 55.7%). At the time accelerated approval was granted, four ongoing phase III randomized studies in patients with advanced breast cancer receiving docetaxel as a first- or second-line therapy were designated as the studies intended to satisfy the requirements to demonstrate clinical benefit under Subpart H.
In 1998, docetaxel received regular approval for the treatment of advanced metastatic breast cancer. Approval was granted on the basis of longer survival demonstrated in a randomized study (TAX304) comparing docetaxel with mitomycin plus vinblastine (Mutamycin/Velban); approval was supported by evidence from a second randomized study (TAX303) comparing docetaxel with doxorubicin (Adriamycin) (7). In TAX304, median survival for patients in the docetaxel treatment arm was almost 3 months longer than that of patients in the mitomycin plus vinblastine arm (11.4 versus 8.7 months; P = .01); time-to-progression and objective response rate also favored patients in the docetaxel arm. In TAX303, objective response rate, but not time-to-progression or overall survival, was better for patients in the docetaxel arm than for patients in the doxorubicin arm. Because a number of patients treated on TAX303 had disease progression after receiving alkylator-containing therapy, the regular approval for docetaxel expanded the indication from treatment of patients whose disease had progressed from anthracycline-based therapy to treatment of patients whose disease had progressed from previous chemotherapy.
In 1996, irinotecan (Camptosar) was granted accelerated approval for second-line treatment of colorectal cancer. Accelerated approval was based on objective response rates measured in three single-arm studies (8). Each study used a weekly dosage schedule. The three studies enrolled a total of 304 evaluable patients with metastatic colorectal cancer who had previously received 5-fluorouracil (5-FU; Adrucil). An objective response rate of 15.0% (95% CI = 10.0% to 20.1%) was observed in 193 patients who received the recommended starting dose of 125 mg/m2. When accelerated approval was granted, the sponsor made a commitment to complete a phase III randomized study comparing irinotecan, 5-FU plus leucovorin (LV), and irinotecan combined with 5-FU plus LV in patients with untreated metastatic colorectal cancer. Subsequently, the sponsor proposed submission of the results of two large, randomized European studies as confirmation of clinical benefit. In one study (9), irinotecan (administered once every 3 weeks) was compared with best supportive care in 279 patients with metastatic colorectal cancer after progression on 5-FU. The median survival of patients who received irinotecan was statistically significantly longer than that of patients who received best supportive care (9.2 versus 6.5 months, respectively; P<.001) (9). In the second study (10), irinotecan was compared with 5-FU administered by infusion in 256 patients who had progressed on first-line 5-FU. Patients who received irinotecan had statistically significantly improved median survival compared with patients who received 5-FU (median survival = 10.8 versus 8.5 months; P = .035). For irinotecan, the population evaluated in the studies submitted for accelerated approval was similar to that evaluated in the studies submitted for regular approval. However, regular approval for irinotecan did expand the indication to include a once-every-3-weeks schedule of administration in addition to the weekly schedule.
In 1998, capecitabine (Xeloda) was granted accelerated approval for the treatment of refractory breast cancer. Approval was based on objective response rate in one single-arm study (11). Of the 162 patients enrolled in the study, more than 90% had received both paclitaxel and an anthracycline-containing regimen. The objective response rate in the 43 patients who had measurable disease resistant to paclitaxel and anthracycline was 25.6% (95% CI = 13.5% to 41.2%). The objective response rate was 18.5% for the 135 patients with measurable disease. The confirmatory randomized study compared the capecitabine plus docetaxel combination with single-agent docetaxel in 511 patients with advanced breast cancer who had disease progression after receiving a prior anthracycline. Compared with patients who received docetaxel alone, patients who received the combination therapy had statistically significantly prolonged median survival (442 versus 352 days; P = .013) and improved time-to-progression and objective response rate.
In 1995, dexrazoxane (Zinecard) was granted accelerated approval for reducing the incidence and severity of doxorubicin-associated cardiomyopathy in women with breast cancer who had received a cumulative doxorubicin dose of 300 mg/m2 (when nearly all responses would have occurred and when the risk of cardiotoxicity began to increase) but who would benefit from continuing doxorubicin therapy. Approval was based on cardioprotection demonstrated in two large studies, in which patients receiving a doxorubicin-based regimen were randomly assigned to receive either dexrazoxane or placebo. Because of concerns raised in one trial regarding statistically significantly lower response rate and shorter time-to-progression for patients in the dexrazoxane arm, dexrazoxane was granted accelerated rather than regular approval for use only after patients had received a cumulative doxorubicin dose of 300 mg/m2. The sponsor was required to demonstrate that continued treatment with doxorubicin and coadministration of dexrazoxane resulted in clinical benefit compared with ending doxorubicin therapy at a cumulative dose of 300 mg/m2. Although the study was initiated, it was terminated after 3 years because of poor accrual. Dexrazoxane was subsequently granted regular approval on the basis of evidence from the literature (1218), including a meta-analysis of five studies that evaluated the benefit of continued anthracycline use.
In 2001, imatinib mesylate (Gleevec) was granted accelerated approval for the treatment of chronic myelogenous leukemia (CML) in blast crisis, in accelerated phase, or in chronic phase after progression on interferon (IFN) treatment. Approval was granted on the basis of results from three single-arm studies (19,20) conducted in patients with Philadelphia chromosomepositive CML. A total of 1027 patients were enrolled on the studies, which evaluated cytogenetic response rate (CMLchronic phase) and hematologic response rate (CMLaccelerated phase and CMLblast crisis) as primary endpoints. The cytogenetic response rate for patients with CMLchronic phase was 53% (95% CI = 49% to 57%), and the hematologic response rates for patients with CMLaccelerated phase and CMLblast crisis were 69% (95% CI = 63% to 75%) and 31% (95% CI = 25% to 37%), respectively. In addition to providing safety and efficacy follow-up of the three single-arm studies, the sponsor also committed to complete a randomized phase III study comparing imatinib to a combination of IFN plus cytarabine in patients with newly diagnosed CML. This randomized study, which was open to enrollment from June 2000 to January 2001, has been completed and submission of its findings has resulted in the accelerated approval of imatinib for first-line treatment of CML.
In 2003, accelerated approval of imatinib mesylate for the treatment of CML in blast crisis, in accelerated phase, or in chronic phase after IFN therapy was converted to regular approval on the basis of the submission of follow-up data. All 532 patients with chronic phase CML were in late chronic phase, with a median time from diagnosis to last follow-up of 32 months. A complete hematologic response rate was achieved in 95% (95% CI = 92.3% to 96.3%) of the patients. The confirmed major cytogenetic response rate was 60% (95% CI = 55.3% to 63.8%). An estimated 87.8% of patients who achieved a major cytogenetic response maintained the response for 2 years after the initial response. After 2 years of treatment, estimated overall survival was 90.8% (95% CI = 88.3% to 93.2%). Hematologic response rates for patients with blast crisis CML and accelerated phase CML were similar to those observed in the initial interim analyses described above. The median duration of hematologic response was 10 months for patients in blast crisis and 28.8 months for patients in accelerated phase.
In 2002, oxaliplatin (Eloxatin) was granted accelerated approval for use in combination with 5-FU/LV on the basis of data from a randomized, three-arm study of oxaliplatin plus infusional 5-FU/LV versus 5-FU/LV alone versus single-agent oxaliplatin in patients with advanced colorectal cancer refractory to first-line treatment with irinotecan and bolus 5-FU/LV (21). The study enrolled 821 patients and had a preplanned interim analysis after 450 patients were enrolled. At the time of this interim analysis, a response rate of 9% (13 of 152) was observed in the combination arm compared with a response rate of 0% (0 of 151) in the 5-FU/LV arm (P = .002). Patients in the combination arm had an approximately 2-month increase in median time-to-progression (4.6 months, 95% CI = 4.2 to 6.1 months) compared with patients in the 5-FU/LV-alone arm (2.7 months, 95% CI = 1.8 to 3.0 months). Phase 4 commitments by the applicant included completion of the three-arm study and completion of first-line, second-line, and adjuvant therapy colorectal cancer trials.
In January 2004, oxaliplatin was granted regular approval on the basis of results from a randomized clinical trial evaluating oxaliplatin in the first-line treatment of advanced colorectal cancer. The trial, sponsored by the National Cancer Institute (NCI) and led by the North Central Cancer Treatment Group, had seven arms at different times during its conduct, four of which were closed because of changes in the standard of care or toxicity or for the purpose of simplifying the study design. During the study, the control arm was changed to irinotecan plus bolus 5-FU/LV. Each arm of the study enrolled more than 260 patients; 267 patients were enrolled on the oxaliplatin plus 5-FU/LVarm, 264 patients were enrolled on the irinotecan plus bolus 5-FU/LV arm, and 264 patients were enrolled on the oxaliplatin plus irinotecan arm. Patients who received the oxaliplatin plus 5-FU/LV regimen had a longer median survival (19.4 months) than patients who received the irinotecan plus bolus 5-FU/LV regimen (14.6 months; P<.001). Time to progression and objective response rate were also better for patients on the oxaliplatin plus 5-FU/LV regimen compared with those in patients on the control irinotecan plus bolus 5-FU/LV regimen.
Accelerated Approval Indications Not Yet Converted to Regular ApprovalStudies Without an Active Comparator
Of the 16 indications that have not yet been converted to regular approvals, 11 accelerated approvals were granted on the basis of studies without an active comparator. These include eight indications based on one or more single-arm studies and three indications in which two dose levels were compared in a randomized setting. In studies that enrolled patients with refractory or relapsed disease, the primary endpoint was objective response rate, which is believed to represent a surrogate endpoint reasonably likely to predict clinical benefit. The list of accelerated approvals in this category is summarized in Table 2.
In 1995, liposomal doxorubicin (Doxil) was granted accelerated approval for second-line treatment of Kaposi sarcoma on the basis of objective response rates [investigator assessment using the modified criteria from the AIDS Clinical Trials Group (22) and indicator lesion assessment for up to five representative indicator lesions] in one open-label, single-arm, multicenter study (23). The original phase 4 commitment trial, which was conducted between 1996 and 2000 with 80 patients enrolled, was a double-blind, randomized study evaluating clinical benefit in patients with AIDS-related Kaposi sarcoma treated with either liposomal doxorubicin or liposomal daunorubicin. Clinical benefit was defined as an improvement in functional activity, pulmonary or gastrointestinal symptoms, Kaposi sarcoma-associated pain despite analgesics, or self-image altered by disfiguring Kaposi sarcoma lesions. However, the introduction of highly active antiretroviral therapy for the treatment of human immunodeficiency virus (HIV) infection made it difficult to distinguish the antitumor effects associated with antiretroviral therapy from those of liposomal doxorubicin.
In 1996, amifostine (Ethyol) was granted accelerated approval for the reduction of cisplatin-associated renal toxicity in patients with advanced nonsmall-cell lung cancer (NSCLC). The approval was granted on the basis of results from a single-arm study in patients with stage IV NSCLC (24). Accelerated rather than regular approval was granted because of the concern that amifostine would protect the tumor from tumor-specific cytotoxicity. A phase III trial of cisplatin plus vinblastine with or without amifostine in patients with stage IIIb or IV NSCLC, which began in December 1994 and was completed in 1999, was designated as a confirmatory study that would fulfill the phase 4 commitment. Although reduced toxicity was demonstrated, the results were insufficient to rule out an effect on antitumor efficacy (i.e., that amifostine did not interfere with the cytotoxic effects of chemotherapy). An international, randomized, double-blind, placebo-controlled study in patients with advanced NSCLC will evaluate the effect of amifostine on nephrotoxicity and non-inferiority of tumor response rate, with non-inferiority in survival as a secondary endpoint.
In 1999, liposomal doxorubicin was granted accelerated approval for the treatment of refractory ovarian cancer. This approval was granted on the basis of objective response rates observed in three single-arm studies (23) of women with metastatic disease, most of whom had progressed or recurred after paclitaxel and platinum-based regimens. At the time of accelerated approval, the sponsor agreed to complete a randomized phase III study (initiated in 1997) of liposomal doxorubicin versus topotecan (Hycamtin) in patients with epithelial ovarian carcinoma after disease progression from first-line, platinum-based chemotherapy (25). A second commitment study was developed to demonstrate superiority in the primary survival endpoint. In September 2002, the Southwest Oncology Group began enrollment to this phase III trial of liposomal doxorubicin plus carboplatin versus single-agent carboplatin in platinum-sensitive patients with recurrent epithelial ovarian or peritoneal carcinoma after disease progression from initial platinum-based chemotherapy.
Denileukin diftitox (Ontak) was granted accelerated approval in 1999 for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the interleukin 2 receptor. Approval was based on results from a randomized study that compared 9 µg/kg/day versus 18 µg/kg/day (given for 5 consecutive days every 21 days) in 71 patients with persistent or refractory disease (26). The objective response rate for the two treatment arms combined was 30% (95% CI = 18% to 41%), with no statistically significant difference in objective response rates between the two arms. The post-approval phase 4 commitment, which was initiated before accelerated approval was granted, is for a randomized, three-arm study with 1 : 2 : 2 randomization to placebo, 9 µg/kg/day, or 18 µg/kg/day that is currently accruing patients in North America, Europe, and Australia.
Temozolomide (Temodar) received accelerated approval in 1999 on the basis of results from a single-arm study of 162 patients with relapsed anaplastic astrocytoma who had disease progression after radiation therapy (27). Many patients had also received previous chemotherapy. An objective response rate of 22% and a complete response of 9% were observed in the 54 patients who had progressed after treatment with both procarbazine and a nitrosourea. The median survival in this population of patients was 15.9 months. At the time that accelerated approval was granted, the phase 4 commitment was to conduct a randomized study of radiation therapy combined with temozolomide or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or radiation therapy plus temozolomide plus BCNU in patients with anaplastic astrocytoma. Although a preliminary study was initiated in June 2000, the combination of radiation therapy plus temozolomide plus BCNU was associated with excessive toxicity and substantial dose reductions, which resulted in termination of this arm of the study. A phase III randomized trial comparing radiation plus temozolomide to radiation plus BCNU was initiated in October 2002.
In 2000, gemtuzumab ozogamicin (Mylotarg) received accelerated approval for second-line treatment of acute myelogenous leukemia (AML) in elderly patients who are not candidates for cytotoxic therapy. Accelerated approval was based on hematologic response observed in three single-arm studies (28). Of a total enrollment of 142 patients, 80 patients were at least 60 years old. The pooled response rate (i.e., complete response and complete response with incomplete platelet recovery) was 30% (95% CI = 22% to 38%). The post-marketing commitment under Subpart H required the conduct of a randomized study of gemtuzumab ozogamicin, daunorubicin, and cytarabine (Cytosar-U) versus daunorubicin and cytarabine combined as induction therapy in patients with de novo CD33-positive AML. Before the phase III study could be initiated, a safe dose and schedule for gemtuzumab ozogamicin administration in combination with daunorubicin and cytarabine had to be established. To that end, two dose-ranging studies are being conducted (29). The planned phase III trial is being developed in conjunction with the Southwest Oncology Group.
In 2001, alemtuzumab (Campath) received accelerated approval on the basis of objective response rate and duration of response in one single-arm study and two additional supportive noncomparative studies. Study 1 enrolled 93 patients with B-cell chronic lymphocytic leukemia (B-CLL) who had been previously treated with alkylating agents and whose disease had progressed with fludarabine (Fludara) treatment (30). The objective response rate was 33% (95% CI = 23% to 43%), and the median response duration was 7 months (95% CI = 5 to 8 months). Two supportive multicenter, open-label, noncomparative studies of alemtuzumab enrolled a total of 56 patients with B-CLL who had been previously treated with fludarabine or other chemotherapies. The objective response rates were 21% (95% CI = 8% to 33%) and 29% (95% CI = 11% to 47%) in each of the two noncomparative studies. A randomized trial designed to evaluate disease-free survival among patients with B-CLL treated with alemtuzumab or chlorambucil (Leukeran) as a first-line therapy was initiated in 2001. The trial is actively accruing patients, with more than 50% of the required patients enrolled.
Imatinib mesylate received accelerated approval in 2002 for the treatment of gastrointestinal stromal tumors. This approval was granted on the basis of the objective response rate observed in a randomized phase II study of imatinib (400 versus 600 mg daily) in patients with metastatic or unresectable malignant gastrointestinal stromal tumors, a disease for which there is no useful available therapy (31,32). The objective response rate for both treatment groups combined was 38% (95% CI = 30% to 46%), with no statistically significant difference between the two groups. At the time of accelerated approval, the sponsor made several phase 4 commitments, including submission of data from two large randomized studies (one U.S and one European) of 400 versus 800 mg daily of imatinib. Each study has completed enrollment of more than 700 patients (33,34).
In 2003, imatinib was granted accelerated approval for the treatment of pediatric patients with chronic-phase CML. This approval was granted after extrapolation from adult data and was based on the findings from two pediatric, open-label, phase I studies that were conducted in 39 patients with chronic-phase CML who had received stem cell transplantation or were resistant to IFN therapy, or patients with Philadelphia chromosomepositive AML, acute lymphocytic leukemia, or CML in blast crisis that was recurrent or refractory to multidrug regimens. In one study, 31 patients were treated with imatinib at doses ranging from 260 to 570 mg/m2/day. In the 13 patients with chronic-phase CML for whom cytogenetic data were available, 11 patients achieved major cytogenetic responses and seven achieved complete cytogenetic responses. In the other study, eight patients were treated with doses ranging from 173 to 360 mg/m2/day. Twoof the three patients with CML achieved complete cytogenetic responses. The rate of complete cytogenetic response at the sponsor's recommended dose in children with CML in chronic phase (pooled from both studies) was 67% (four of six). The sponsor's phase 4 commitment is to complete a report on the safety, efficacy, and pharmacokinetic data from the ongoing NCI-sponsored Children's Oncology Group study of imatinib in patients with newly diagnosed or relapsed chronic-phase CML.
Gefitinib (Iressa) received accelerated approval in 2003 as third-line therapy for locally advanced or metastatic NSCLC on the basis of results from a multicenter, randomized U.S. study comparing 250 to 500 mg/day in patients whose disease had progressed after at least two chemotherapy regimens that included a platinum drug and docetaxel (35,36). Of 216 patients receiving gefitinib, 142 patients were considered appropriate third-line candidates because they had either documented disease progression on platinum and docetaxel therapies or had shown unacceptable toxic responses to these agents. The objective response rate for the two dose levels combined was 10.6% (95% CI = 6.0% to 16.8%). Objective responses were also observed in a second phase II study involving patients with less refractory disease. However, results from two large randomized studies (37,38) showed no benefit from adding gefitinib to doublet, platinum-based chemotherapy in the first-line setting. Post-marketing commitments include a randomized study comparing survival between two armsgefitinib plus best supportive care versus placebo plus best supportive carein patients with NSCLC refractory or intolerant to chemotherapy, a randomized study comparing survival among patients with NSCLC treated with gefitinib or with docetaxel, and a randomized, double-blind, placebo-controlled trial comparing symptom improvement with gefitinib treatment versus best supportive care among patients with refractory, symptomatic, advanced NSCLC.
Bortezomib (Velcade) received accelerated approval in 2003 for the treatment of multiple myeloma patients who received at least two therapies and had demonstrated disease progression on the most recent therapy (39). The primary efficacy study enrolled 202 patients. Bortezomib was administered at a dose of 1.3 mg/m2/day twice weekly for 2 weeks every 21 days (i.e., one cycle) for a maximum of eight treatment cycles. Among the 188 patients evaluable for response, the objective response rate was 27.7% (95% CI = 21% to 35%) using Blade criteria (40), and the clinical remission rate was 17.6% (95% CI = 12% to 24%) using Southwest Oncology Group criteria (41). A small doseresponse study was performed in 54 patients with multiple myeloma who received either 1 or 1.3 mg/m2/day twice weekly for 2 of 3 weeks. Objective response rates of 30% and 38%, respectively, using Southwest Oncology Group criteria, were observed. Phase 4 commitments include submitting final reports of two ongoing studies in patients with previously treated multiple myeloma, initiating and completing a randomized study in previously untreated patients with multiple myeloma, and providing follow-up information to further characterize the frequency, severity, and reversibility of peripheral neuropathy in multiple myeloma patients treated with bortezomib.
Accelerated Approval Indications Not Yet Converted to Regular Approval Based on Randomized Studies With an Active or Placebo Control
For five of the 16 drugs that have received accelerated approval but have not yet converted to regular approval, accelerated approval was granted on the basis of studies with an active or placebo control (Table 3). In the randomized setting, a variety of endpoints were evaluated according to the specific disease setting.
In 1999, liposomal cytarabine (DepoCyt) was approved for the intrathecal treatment of lymphomatous meningitis. Approval was based on data from a randomized, multicenter, multiarm study of liposomal cytarabine (50 mg) administered every 2 weeks versus standard intrathecal chemotherapy administered twice a week to patients with solid tumors, lymphoma, or leukemia (42). For patients with lymphoma, standard intrathecal chemotherapy consisted of 50 mg of unencapsulated cytarabine given twice a week. Of the 99 patients enrolled on the study, 33 had lymphoma, and of these, seven of 17 (41%) in the experimental arm compared with one of 16 (6%) in the uncapsulated cytarabine arm had a complete cytogenetic response. The phase 4 commitment was to conduct a clinical study to determine the patient benefit and safety of liposomal cytarabine and to include a pharmacokinetic substudy. A randomized study of liposomal cytarabine versus cytarabine (lymphoma) or liposomal cytarabine versus methotrexate (other diseases) was initiated in March 2001. A delay in accrual occurred due to a product manufacturing recall, which has been resolved. The study continues to enroll patients in the United States and Europe.
Celecoxib (Celebrex) received accelerated approval in 1999 for the reduction of adenomatous polyps on the basis of results from a randomized, double-blind, placebo-controlled study in patients with familial adenomatous polyposis (43). Eighty-three patients were randomly assigned to receive celecoxib at 400 mg twice daily, celecoxib at 100 mg twice daily, or placebo. The endpoint of interest was reduction in the number of colorectal polyps at 6 months. The mean reduction in number of polyps observed at 6 months was 28% for patients who received celecoxib at 400 mg twice daily, 12% for patients who received celecoxib at 100 mg twice daily, and 5% for patients who received placebo. The difference between the celecoxib at 400 mg twice daily and placebo arms was statistically significant (P = .003). The sponsor made two phase 4 commitments. The first commitment was to conduct a randomized, placebo-controlled study in adolescents with familial adenomatous polyposis who are genotypically positive for the APC mutation but phenotypically negative for polyps, and the second commitment was to establish a long-term registry of clinical outcomes in patients with familial adenomatous polyposis aged 12 years or older receiving celecoxib. Registry information is to be submitted annually to the FDA. Before initiating the phase III randomized study in adolescent patients, the sponsor initiated a safety and dose-ranging phase I study of celebrex in patients aged 10 to 14 years with genotypic evidence of APC mutation and/or clinical polyposis.
In 2002, ibritumomab tiuxetan (Zevalin) received accelerated approval for the treatment of relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin lymphoma (NHL). Approval was granted on the basis of an evaluation of response in a randomized study that compared an ibritumomab tiuxetan therapeutic regimen to a rituximab regimen (Rituxan). In this study, 143 patients were randomly assigned to receive either a Zevalin therapeutic regimen (Step 1: rituximab + In-111 ibritumomab tiuxetan; Step 2: rituximab + Y-90 ibritumomab tiuxetan) or rituximab weekly for 4 doses. The objective response rate, based on international workshop response criteria (44), was 80% for patients in the Zevalin arm compared with 56% for patients in the rituximab arm (P = .002) (44). The sponsor has two phase 4 commitments. One is to conduct a randomized, multicenter study to establish the clinical benefit of the Zevalin therapeutic regimen used in combination with Rituxan compared with Rituxan therapy alone in patients who had relapsed following chemotherapy or who had refractory NHL. The trial was initiated in March 2003 and is actively accruing patients. The second is to conduct a study that will assess the safety and efficacy of the Zevalin therapeutic regimen in patients with transformed CD20-positive B-cell NHL based on establishing durable overall responses in this population.
In 2002, anastrozole (Arimidex) received accelerated approval on the basis of an evaluation of the randomized, double-blind Arimidex or Tamoxifen Alone or in Combination (ATAC) trial (45) comparing tamoxifen (Nolvadex) at 20 mg per day, anastrozole at 1 mg per day, and anastrozole in combination with tamoxifen as adjuvant treatment for postmenopausal women with operable breast cancer. The primary endpoint was recurrence-free survival. At the time of the efficacy analysis, 9366 women had been enrolled on the trial, with a median of 31 months of treatment and a median follow-up of 33 months. Recurrence-free survival was improved in the anastrozole arm compared with the tamoxifen arm (12.2% versus 10.2% recurrence rate; hazard ratio = 0.83; P = .014). Recurrence-free survival in the combination treatment arm was similar to that in the single-agent tamoxifen arm. Phase 4 commitments include submission of a complete report of the updated ATAC data. The sponsor was required to conduct a substudy of hyperlipidemia in patients on the ATAC study and to conduct a double-blind, randomized comparison study evaluating bisphosphonate therapy with anastrozole in early breast cancer patients.
Imatinib mesylate received accelerated approval in 2002 for the treatment of newly diagnosed patients with CML on the basis of time-to-progression data from a randomized study comparing imatinib to IFN plus cytarabine (46). The trial enrolled 1106 patients. Crossover was allowed for patients who lost a complete hematologic response or major cytologic response, did not achieve a major cytogenetic response at 12 months, or who were intolerant of IFN therapy. The imatinib arm showed statistically significantly superior results for time-to-accelerated-phase or blast crisis, progression-free survival, complete hematologic response rate, and cytogenetic response rate (median follow-up of 14 months). The phase 4 commitment requires the sponsor to provide interval follow-up safety and efficacy information annually for 3 years and survival and adverse event data for an additional 3 years.
Accelerated Approval With Uncertainty Regarding Ultimate Outcome
Although accelerated approval, in most cases, is based on a reasonable surrogate endpoint, it can also be based on a clinical benefit that is not the ultimate purpose of treatment, such as survival. In these instances, the sponsor is required to study the drug further to determine the ultimate outcome. Four oncology indications in this class have received approval under the Subpart H regulations (Table 4). All four drugs (dexrazoxane, amifostine, anastrozole, and imatinib mesylate) have been discussed above.
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Although improved disease-free survival may be considered clinical benefit in adjuvant hormonal breast cancer treatment, patients in the anastrozole study (45) had received only a median of 31 months of a planned 60 months of treatment at the time of study analysis. The comparator, tamoxifen, has been shown to improve survival in this setting. Therefore, uncertainty about the ultimate outcome necessitated accelerated approval under Subpart H, with follow-up of the same study as a phase 4 commitment.
The accelerated approval of imatinib mesylate for first-line treatment of CML was based primarily on longer time-to-accelerated-phase or blast crisis with imatinib mesylate treatment and was supported by hematologic and/or cytogenetic response data. Although longer time-to-accelerated-phase or blast crisis may be considered clinical benefit, follow-up time was very short and few of the expected events had occurred. The required additional evidence regarding effect on ultimate outcome will be provided by evaluation of time-to-accelerated-phase or blast crisis and survival after a longer follow-up duration. Follow-up safety and efficacy information will be provided annually for 3 additional years and survival data will be provided for another 3 years thereafter.
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Measures that would ensure timely completion of the confirmatory studies after accelerated approval is granted should be part of the development plan. Accelerated approval provides the commercial drug to patients and can interfere with patient accrual to the confirmatory study, especially when the confirmatory trial is in the same disease population as the drug's accelerated approval. Useful measures to assist in study accrual and completion include the addition of study sites or plans to conduct the confirmatory study in countries where the drug may not yet be commercially available. For example, the phase 4 commitment study for denileukin diftitox, which was initiated before accelerated U.S. approval was granted, has since been expanded from the United States to sites in Europe and Australia to increase accrual. The conversion of irinotecan from accelerated approval to regular approval was based on two large, randomized European studies (one comparing irinotecan to best supportive care) that would have had potential accrual difficulties in the United States after the approval of irinotecan but were required for approval by the European authorities. When considering expanding accrual to sites outside the United States, the generalizability of the population to the U.S. population and the availability of expert training and care, especially for the administration of complex therapies (i.e., radioimmunotherapy or stem cell transplantation) should be assessed.
Early discussions with the FDA regarding plans for confirmatory trials may allow evaluation of different doses, drug combinations, or patient populations. Because confirmatory trials may examine the approved drug in combination with other agents, additional phase I studies may be required before the initiation of confirmatory trials. For example, the post-marketing commitment for gemtuzumab ozogomicin specified that a randomized trial comparing standard induction therapy with cytarabine plus daunorubicin to a combination including gemtuzumab be conducted. Before such a trial could be implemented, dose-ranging studies were needed, which are now being conducted. In the case of temozolomide, the tolerability study of temozolomide plus BCNU did not support starting the phase III trial with the combination of radiation therapy, temozolomide, and BCNU as a treatment arm because of excessive toxicity, delaying conduct of the confirmatory study.
Accelerated approval is commonly based on objective response rates in single-arm studies in patients with refractory disease, with confirmatory studies conducted in related populations, usually in patients with less refractory or an earlier stage of disease. This approach may expedite drug availability to patients with life-threatening disease because single-arm studies are completed and analyzed more rapidly than large, randomized trials.
Because the surrogate endpoint used for accelerated approval must be "reasonably likely" to predict clinical benefit, nominal response rates in heavily pretreated patients may make this clinical prediction difficult. Moreover, findings in refractory populations may not be relevant to the general population or to other populations that may benefit from the drug. However, responses in patients with refractory disease who have experienced progression on numerous therapies may help to identify novel agents with unique mechanisms of action. The single-arm setting does not allow for an interpretable assessment of time-to-event endpoints, such as survival or time-to-progression, and it may be difficult to completely evaluate the toxicity profile in this setting. The approval of gefitinib as a third-line therapy for NSCLC illustrates the difficulties in characterizing toxicities in heavily pretreated patients enrolled on single-arm trials, in which the potential for pulmonary toxicity was difficult to assess because of the advanced stage of disease and the effects of previous treatments, such as chemotherapy and radiotherapy.
An alternative to the single-arm trial in populations with refractory disease is a randomized study that could support accelerated approval based on an interim analysis of one or more surrogate endpoints (e.g., response rate or time-to-progression). At the completion of the randomized study, an established clinical benefit endpoint such as survival would be evaluated. This design ensures completion of the confirmatory study and allows clinical benefit to be assessed in the same population as that in the accelerated approval indication. The randomized setting also allows for evaluation of time-to-event endpoints and a more comprehensive evaluation of the toxicity profile.
The above strategy has been used regularly in the evaluation of antiHIV drugs. Two randomized studies (each with approximately 1000 patients) are usually required for such evaluations. The surrogate endpoint for accelerated approval is HIV viral load assessed at 24 weeks. Regular approval is granted based on the effect on viral load at 48 weeks (47). The same study thus provides support for accelerated and regular approval. It should be noted that the use of an analogous laboratory surrogate to support accelerated approval as described for HIV has not, to date, occurred in the setting of oncology drug approvals.
In oncology, the approval of oxaliplatin as a component of combination second-line therapy for advanced colorectal cancer demonstrated the use of an interim analysis from a randomized trial to support accelerated approval. Accelerated approval was based on objective response rate and time-to-progression evaluated at a prespecified interim analysis, with the proposed demonstration of clinical benefit (survival) at study completion (48).
Randomized studies provide additional advantages and disadvantages for evaluating cancer therapies. Cytostatic agents, many of which may not produce tumor responses, are probably best assessed by time-to-event endpointsendpoints that cannot be evaluated in single-arm trials. Randomized studies also allow interpretation of "add-on" trial designs, in which the new drug is added to standard therapy. Randomized trials allow the use of placebo controls, as noted in the discussions of celecoxib and dexrazoxane. However, survival results may be confounded by crossover and subsequent therapies given at the time of tumor progression. For example, crossover may confound the final analysis of the randomized trial that was the basis for the approval of imatinib mesylate for the first-line treatment of CML.
In conclusion, the accelerated approval program in oncology has been successful in making 18 different products available to patients for 22 different cancer treatment indications. The use of single-arm studies for accelerated approval allows for the rapid evaluation of novel agents, usually in patients with refractory disease. Randomized studies allow for the evaluation of populations with less refractory disease, add-on designs, confirmation of clinical benefit in the same population as that used for accelerated approval, a larger and more precise safety database, and the examination of time-to-event endpoints.
Both single-arm studies and randomized studies may provide evidence to support accelerated approval. It is useful to discuss development plans including the design, conduct, and analysis of confirmatory studies with the FDA early in the development process. These studies are viewed as part of a comprehensive drug development plan that includes studies that might lead to accelerated approval and the confirmatory studies.
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Manuscript received March 8, 2004; revised May 12, 2004; accepted August 6, 2004.
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