A Sponsor's Perspective on the Contribution of Regulatory-Required Observational Post-Marketing Studies to Understanding Human Drug Product Benefit/Risk in Japan.

BACKGROUND: Following marketing authorization in Japan, for almost all new drugs or new indications, postmarketing studies (PMS) are a regulatory requirement. These PMS focus on accrual of a defined number of cases with data being collected for a predetermined period after approval to confirm efficacy/effectiveness, safety, and quality in the Japanese population. In contrast to other regions where PMS are only required to address a specific scientific uncertainty, in Japan, PMS are often required regardless of any specific scientific uncertainty, and therefore, their scientific value is unclear. OBJECTIVES: To determine the contribution to the understanding of benefit/risk of PMS conducted by Pfizer in Japan over 2000-2020 for Pharmaceuticals and Medical Devices Agency (PMDA) reexamination. METHODS: A retrospective analysis of all Pfizer Japan postmarketing studies (PMS) during 2000-2020 was performed. Available Pfizer clinical study reports (CSRs) and PMDA reexamination reports (RERs) were reviewed for key safety findings. The primary analysis was conducted on the subset of PMS that had both an English CSR and a discussion of that PMS in the relevant RER issued by the PMDA, which was subsequently translated into English by a professional translation vendor. Reexamination outcome is included in each RER and served to demonstrate the impact of the study of the benefit/risk profile of the drug. RESULTS: A total of 79 PMS for 43 different drug products across therapy areas enrolled a total of 98,035 patients. The 79 PMS comprised 34 general drug use investigation (GDUI) studies and 45 special investigation (SI) studies. The primary analysis involved 37 PMS with a CSR and RER available in English (40,470 patients); all of which were observational in design. For 31 of 37 PMS, the RER concluded the overall adverse drug reaction (ADR) rate in the PMS was nominally lower than in the phase 3 program. Unlabeled ADRs were reported in 28 of 37 PMS; however, no new safety concerns requiring regulatory action arose from any PMS. The PMDA did not require additional risk minimization measures for any of the 43 drug products studied in any of the 79 PMS assessed. Japan PMS data were consistent with prior global data with no evidence of clinically meaningful differences in safety in Japanese patients. In all cases, the reexamination outcome was category 1 ("usefulness is confirmed"). CONCLUSIONS: The reexamination process did not result in regulatory changes for any of the examined drugs. The Japan new-drug application (J-NDA) review and approval process, including implementation of the initial Japan product label, assures acceptable benefit/risk at the time of approval such that mandatory GDUI or SI studies for all products should be reconsidered. In the case of genuine scientific uncertainty to the extent that the benefit/risk of the product is not clear, a PMS is warranted.

The Relationship Between Development Start Lag and Approval Lag in Oncology Drug Development in Japan.

BACKGROUND: The delay of initiation of clinical development is considered a causes of delay of approval of drugs (drug lag) in Japan. METHODS: For oncology drugs newly approved between 2000 and 2012 in Japan, a possible impact of delay of initiation of clinical development (development start lag [DSL]) on delay of approval (approval lag [AL]) was investigated, focusing on the delay from the US timelines. The equation defining the relationship between the DSL and AL of 33 oncology drugs was calculated by using simulation models, then the Pearson coefficient of correlation between parameters was calculated. RESULTS: From the analysis of all drugs investigated, a positive relationship between the DSL and AL was suggested. However, the relationship seemed to have 2 phases, including a flat phase, followed by a linearly increased phase with a breakpoint at 2340 DSL days (approximately 6.4 DSL years). CONCLUSIONS: Shortening the DSL is important for reducing large AL, but it is not necessary to eliminate the DSL completely for the purpose of minimizing the AL.

Randomized trial and pharmacokinetic study of pegfilgrastim versus filgrastim after dose-intensive chemotherapy in young adults and children with sarcomas.

PURPOSE: To compare the effectiveness, tolerance, and pharmacokinetics of a single dose of pegfilgrastim to daily filgrastim in children and young adults with sarcomas treated with dose-intensive combination chemotherapy. EXPERIMENTAL DESIGN: Patients were randomized to receive a single dose of 100 mcg/kg of pegfilgrastim s.c. or 5 mcg/kg/day of filgrastim s.c., daily until neutrophil recovery after two treatment cycles with vincristine, doxorubicin, and cyclophosphamide (VDC) and two cycles of etoposide and ifosfamide (IE). The duration of severe neutropenia (absolute neutrophil count, < or =500/mcL) during cycles 1 to 4 and cycle duration for all cycles were compared. Pharmacokinetics of pegfilgrastim and filgrastim and CD34+ stem cell mobilization were studied on cycle 1. Growth factor-related toxicity, transfusions, and episodes of fever and neutropenia and infections were collected for cycles 1 to 4. RESULTS: Thirty-four patients (median age, 20 years; range 3.8-25.8) were enrolled, and 32 completed cycles 1 to 4. The median (range) duration of absolute neutrophil count of <500/mcL was 5.5 (3-8) days for pegfilgrastim and 6 (0-9) days for filgrastim (P = 0.76) after VDC, and 1.5 (0-4) days for pegfilgrastim and 3.75 (0-6.5) days for filgrastim (P = 0.11) after IE. More episodes of febrile neutropenia and documented infections occurred on the filgrastim arm. Serum pegfilgrastim concentrations were highly variable. Pegfilgrastim apparent clearance (11 mL/h/kg) was similar to that reported in adults. CONCLUSION: A single dose per cycle of pegfilgrastim was well tolerated and may be as effective as daily filgrastim based on the duration of severe neutropenia and number of episodes of febrile neutropenia and documented infections after dose-intensive treatment with VDC and IE.

Lenalidomide in combination with dexamethasone for the treatment of multiple myeloma after one prior therapy.

PURPOSE: Lenalidomide (CC-5013, Revlimid; Celgene Corporation, Summit, NJ), a thalidomide analogue, was granted approval by the U.S. Food and Drug Administration (FDA) on June 29, 2006, for use in combination with dexamethasone in patients with multiple myeloma (MM) who have received at least one prior therapy. The FDA approved lenalidomide with a restricted distribution program, RevAssist. EXPERIMENTAL DESIGN: In two randomized, double-blind, multicenter studies, the combination of lenalidomide and dexamethasone (LD) was compared with placebo and dexamethasone (PD) in patients with MM who had received at least one prior therapy. The primary endpoint was time to progression (TTP). RESULTS: Following a prespecified interim analysis of TTP, an independent data-monitoring committee advised the sponsor to halt the two studies. For both studies, the interim analysis for efficacy revealed a statistically significant longer TTP with LD than with PD. The most clinically relevant grade 3 and 4 adverse events that occurred more frequently in the LD arm were neutropenia, thrombocytopenia, deep vein thrombosis, pulmonary embolism, and atrial fibrillation. Thrombotic or thromboembolic events, including deep vein thrombosis, pulmonary embolism, thrombosis, and intracranial venous sinus thrombosis were reported more frequently in patients treated with LD than with PD. CONCLUSIONS: The FDA approved lenalidomide based on interim results from two multicenter, placebo-controlled, randomized trials comparing the combination of LD with PD that revealed a longer TTP with LD than with PD. The major toxicity observed during these trials was myelosuppression. The serious toxicities included thromboembolic events. Lenalidomide is only available under the RevAssist Program.

Tasigna for chronic and accelerated phase Philadelphia chromosome--positive chronic myelogenous leukemia resistant to or intolerant of imatinib.

PURPOSE: This Food and Drug Administration (FDA) approval report describes the data and analyses leading to the approval by the FDA of nilotinib (Tasigna, AMN-107; Novartis Pharmaceuticals Corporation), an inhibitor of Bcr-Abl tyrosine kinase, for the treatment of chronic-phase (CP) and accelerated-phase (AP) chronic myelogenous leukemia (CML) resistant to or intolerant of imatinib. EXPERIMENTAL DESIGN: The FDA approval of the efficacy and safety of nilotinib was based on the results of an ongoing single-arm, open-label, phase 2 clinical trial. The primary end point for CML-CP was unconfirmed major cytogenetic response. The efficacy end point for CML-AP was confirmed hematologic response. RESULTS: The major cytogenetic response rate in 232 evaluable CP patients was 40% (95% confidence interval, 33%, 46%). The hematologic response rate in 105 evaluable AP patients was 26% (95% confidence interval, 18%, 35%). The median duration of response has not been reached for both CML-CP and CML-AP responding patients. In CML-CP patients, the common serious drug-related adverse reactions were thrombocytopenia and neutropenia. In CML-AP patients, the common serious drug-related adverse reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia. Nilotinib prolongs the QT interval and sudden deaths have been reported; these risks and appropriate risk minimization strategies are described in a boxed warning on the labeling. CONCLUSIONS: On October 29, 2007, the U.S. FDA granted accelerated approval to nilotinib (Tasigna) for use in the treatment of CP and AP Philadelphia chromosome positive CML in adult patients resistant to or intolerant of prior therapy that included imatinib.

Ixabepilone in combination with capecitabine and as monotherapy for treatment of advanced breast cancer refractory to previous chemotherapies.

PURPOSE: To describe the considerations leading to marketing approval of ixabepilone in combination with capecitabine and as monotherapy for the treatment of advanced breast cancer that is refractory to other chemotherapies. EXPERIMENTAL DESIGN: Data from one randomized multicenter trial comparing combination therapy with ixabepilone and capecitabine to capecitabine alone were analyzed for support of the combination therapy indication. For monotherapy, a single-arm trial of ixabepilone was analyzed. Supporting data came from an additional single-arm combination therapy study and two single-arm monotherapy studies. RESULTS: In patients with metastatic or locally advanced breast cancer who had disease progression on or following an anthracycline and a taxane, ixabepilone plus capecitabine showed an improvement in progression-free survival compared with capecitabine alone {median progression-free survival, 5.7 [95% confidence interval (95% CI), 4.8-6.7] versus 4.1 (95% CI, 3.1-4.3) months, stratified log-rank P < 0.0001; hazard ratio, 0.69 (95% CI, 0.58-0.83)}. As monotherapy for patients who had disease progression on or following an anthracycline, a taxane, and capecitabine, ixabepilone as monotherapy showed a 12% objective response rate by independent blinded review and 18% by investigator assessment. The major toxicities from ixabepilone therapy were peripheral neuropathy and myelosuppression, particularly neutropenia. CONCLUSIONS: On October 16, 2007, the Food and Drug Administration approved ixabepilone for injection in combination with capecitabine or as monotherapy for the treatment of patients with advanced breast cancer who have experienced disease progression on previous chemotherapies.

Dexrazoxane (Totect): FDA review and approval for the treatment of accidental extravasation following intravenous anthracycline chemotherapy.

Management of anthracycline extravasation is problematic and most reports are anecdotal. On September 6, 2007, the U.S. Food and Drug Administration approved Totect 500 mg (dexrazoxane hydrochloride for injection) for the treatment of extravasation resulting from i.v. anthracycline chemotherapy. In two studies, a total of 57 evaluable patients experienced extravasation from peripheral vein or central venous access sites with local swelling, pain, or redness. The presence of anthracycline in skin biopsy tissue was confirmed by tissue fluorescence, and treatment with a 3-day schedule of dexrazoxane began within 6 hours of the event. The primary endpoint was a reduction in the need for surgical intervention. Only one patient required surgical repair of the injury site, and late sequelae in the remainder were absent or mild. Also, the sponsor, TopoTarget A/S, Copenhagen, Denmark, performed controlled nonclinical studies in support of dexrazoxane dose and timing for the reduction of tissue injury resulting from anthracycline extravasation. For this uncommon but serious complication of anthracycline therapy, the need for surgical intervention was 1.7% with this regimen.

Good clinical practice and the conduct of clinical studies in pediatric oncology.

This article discusses the principles that guide good clinical practice standards, with particular emphasis on how they to relate to pediatric oncology research and recent efforts at harmonization. The authors review the clinical trials process and the roles of the participants, highlighting the pivotal role of the clinical investigator and the research team, and briefly review the historical aspects of drug development regulations in the United States and the current regulatory paths for pediatric oncology drug development. Where relevant, historical events that underlie many of the regulations and their current applications are described, and practical examples are provided.

Liposomal doxorubicin in combination with bortezomib for relapsed or refractory multiple myeloma.

PURPOSE: On May 17, 2007, doxorubicin HCl liposome injection (Doxil) in combination with bortezomib (Velcade) received approval from the US Food and Drug Administration (FDA) for the treatment of relapsed or refractory multiple myeloma after at least one prior therapy that has not included bortezomib. Liposomal doxorubicin's efficacy and safety were demonstrated in a phase III, randomized, multicenter, international trial comparing the combination of this agent plus bortezomib vs bortezomib alone in multiple myeloma patients who had not previously received bortezomib and had received at least one prior therapy. Here we summarize the FDA review of the data that support this approval. EXPERIMENTAL DESIGN AND RESULTS: An interim analysis of time to disease progression (TTP), the primary endpoint, was conducted after 249 TTP events in this study that randomized 324 patients to liposomal doxorubicin plus bortezomib treatment and 322 patients to bortezomib monotherapy. Time to progression was significantly prolonged in the combination arm (median TTP = 9.3 months) compared with bortezomib monotherapy (median TTP = 6.5 months), P < .0001 (log-rank test); hazard ratio = 0.55 (95% confidence interval = 0.43-0.71). The response rates were similar between the two arms and not statistically different; however, among responding patients, the median duration of response was longer with the combination--10.2 months compared to 7.0 months in the monotherapy arm. Adverse reactions occurred more frequently with the combination therapy. As compared to the monotherapy, frequent grade 3/4 adverse reactions with the combination were neutropenia and thrombocytopenia. CONCLUSIONS: Liposomal doxorubicin received FDA approval for use in combination with bortezomib in patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

Bortezomib for the treatment of mantle cell lymphoma.

PURPOSE: To describe the Food and Drug Administration review and marketing approval considerations for bortezomib (Velcade) for the treatment of patients with mantle cell lymphoma. EXPERIMENTAL DESIGN: Food and Drug Administration reviewed a multicenter study of bortezomib in 155 patients with progressive mantle cell lymphoma after at least one prior therapy. RESULTS: Seventy-seven percent were stage IV, and 75% had one or more extranodal sites of disease. Prior therapy included an anthracycline or mitoxantrone, cyclophosphamide, and rituximab. Median age was 65 years. All received bortezomib 1.3 mg/m(2) i.v. on days 1, 4, 8, and 11 of each 3-week cycle. The primary end point was response. Response and progression were determined by independent review of serial computed tomography scans using International Lymphoma Workshop Response Criteria. The overall response rate was 31%, including complete response (CR) plus CR unconfirmed (CRu) plus partial response; median response duration was 9.3 months. The CR plus CRu response rate was 8% with a median duration of 15.4 months. Adverse events were similar to those observed previously for bortezomib. The most commonly reported treatment-emergent adverse events were asthenia (72%), peripheral neuropathies (55%), constipation (50%), diarrhea (47%), nausea (44%), and anorexia (39%). The most common adverse event leading to discontinuation was neuropathy. CONCLUSIONS: Bortezomib received regular approval for the treatment of patients with mantle cell lymphoma in relapse after prior therapy.

Vorinostat for treatment of cutaneous manifestations of advanced primary cutaneous T-cell lymphoma.

PURPOSE: To discuss vorinostat approval for treatment of cutaneous manifestations of advanced cutaneous T-cell lymphoma (CTCL). EXPERIMENTAL DESIGN: Data from 1 single-arm, open-label, multicenter pivotal trial and 11 other trials submitted to support the new drug application for vorinostat in the treatment of advanced primary CTCL were reviewed. The pivotal trial assessed responses by changes in overall skin disease score using a severity-weighted assessment tool (SWAT). Vorinostat could be considered active in CTCL if observed response rate was at least 20% and the lower bound of the corresponding 95% confidence interval (95% CI) excluded 5%. Patients reported pruritus relief using a questionnaire and a visual analogue scale. RESULTS: The pivotal trial enrolled 74 patients with stage IB or higher CTCL. Median number of prior treatments was 3, and 61 patients (82%) had stage IIB or higher disease. The objective response rate in the skin disease assessed by change in the overall SWAT score from the baseline was 30% (95% CI, 18.5 to 42.6) in patients with stage IIB or higher disease. Median response duration (end of response defined by 50% increase in SWAT score from the nadir) was 168 days. Median time to tumor progression was 148 days for overall population and 169 days for patients with stage IIB or higher disease. Assessment of pruritus relief was considered unreliable. CONCLUSIONS: Vorinostat showed activity in CTCL, and skin responses were a clinical benefit. Vorinostat was approved for treatment of cutaneous manifestations of CTCL. A nonblinded, single-arm trial did not allow a reliable assessment of pruritus relief.

Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma.

PURPOSE: To describe the Food and Drug Administration (FDA) review and approval of sunitinib malate (Sutent). Sunitinib received regular approval for the treatment of gastrointestinal stromal tumor (GIST) after disease progression or intolerance to imatinib mesylate (Gleevec). Additionally, sunitinib received accelerated approval for the treatment of advanced renal cell carcinoma. EXPERIMENTAL DESIGN: For the GIST indication, FDA reviewed data from a randomized, placebo-controlled trial with supportive evidence from a single-arm study. For the advanced renal cell carcinoma indication, FDA reviewed data from two single-arm studies of patients with cytokine-refractory metastatic renal cell carcinoma. RESULTS: In patients with imatinib refractory or intolerant GIST, time-to-tumor progression of sunitinib-treated patients was superior to that of placebo-treated patients. Median time-to-tumor progression of sunitinib-treated patients was 27.3 weeks, compared with 6.4 weeks for placebo-treated patients (P < 0.0001). Partial responses were observed in 6.8% of sunitinib-treated patients. In patients with metastatic renal cell carcinoma, partial responses were observed in 25.5% (95% confidence interval, 17.5, 34.9) and 36.5% (95% confidence interval, 24.7, 49.6) of patients treated with sunitinib. Median response durations were 27.1 and 54 weeks. The most common adverse events attributed to sunitinib included diarrhea, mucositis, skin abnormalities, and altered taste. Reductions in left ventricular ejection fraction and severe hypertension were also more common in sunitinib-treated patients. CONCLUSIONS: On January 26, 2006, the FDA approved sunitinib for the treatment of patients with imatinib refractory or intolerant GIST. Accelerated approval was granted for the treatment of advanced renal cell carcinoma.

Food and Drug Administration drug approval summary: Sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma.

On January 26, 2006, sunitinib (Sutent) received regular approval as monotherapy for the treatment of patients with gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate (Gleevec). Time-to-tumor progression (TTP) of sunitinib-treated patients was superior to that of placebo-treated patients. Median TTP of sunitinib-treated patients was 27.3 weeks, compared with 6.4 weeks for placebo-treated patients (p < .0001). Partial responses were observed in 6.8% of sunitinib-treated patients and no placebo-treated patients. Sunitinib also received accelerated approval on January 26, 2006, as monotherapy for treatment of advanced renal cell carcinoma (RCC). In two single-arm trials of sunitinib in patients with metastatic RCC, partial responses were observed in 25.5% (95% confidence interval [CI], 17.5, 34.9) and 36.5% (95% CI, 24.7, 49.6) of patients. Median response durations in the two trials were 27.1 weeks (95% CI, 24.4, incalculable) and 54 weeks (95% CI, 34.3, 70.1). Treatment-emergent adverse events in sunitinib-treated patients included diarrhea, mucositis, skin abnormalities, altered taste, electrolyte abnormalities, hypertension, and diminution in left ventricular ejection fraction. Cardiac safety of sunitinib in patients with preexisting cardiac abnormalities remains unknown. Based on nonclinical findings, physicians prescribing sunitinib should monitor for adrenal insufficiency in patients who undergo stressors such as surgery, trauma, or severe infection. Caution should be exercised when administering sunitinib in combination with known CYP3A4 inducers or inhibitors.

Population pharmacokinetic-based dosing of intravenous busulfan in pediatric patients.

The objective of this study was to characterize the pharmacokinetics (PK) of intravenous busulfan in pediatric patients and provide dosing recommendations. Twenty-four pediatric patients were treated with intravenous busulfan, 1.0 or 0.8 mg/kg for ages < or = 4 years or > 4 years, respectively, 4 times a day for 4 days. Dense PK sampling was performed. Body weight, age, gender, and body surface area were explored for effects on PK, and Monte Carlo simulations were performed to assess different dosing regimens. The PK of intravenous busulfan was described by a 1-compartment model with clearance of 4.04 L/h/20 kg and volume of distribution of 12.8 L/20 kg. Simulations indicated that the mg/kg and mg/m2 regimens were similar and achieved the desired target exposure in approximately 60% of patients. This model suggests that patients < or = 12 kg should be dosed at 1.1 mg/kg and those > 12 kg dosed at 0.8 mg/kg. Therapeutic drug monitoring and dose adjustment will further improve therapeutic targeting.

Topotecan in combination with cisplatin for the treatment of stage IVB, recurrent, or persistent cervical cancer.

PURPOSE: Topotecan, a camptothecin analog previously approved for the treatment of ovarian cancer and small-cell lung cancer, was granted regular approval by the US Food and Drug Administration (FDA) on June 14, 2006, for use in combination with cisplatin to treat women with stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. The purpose of this summary is to review the database supporting this approval. EXPERIMENTAL DESIGN: In a randomized multicenter study enrolling 293 eligible patients, topotecan plus cisplatin (TC) was compared with cisplatin monotherapy. The TC regimen consisted of cisplatin 50 mg/m2 IV over 1 hour on day 1 and topotecan 0.75 mg/m2 IV over 30 minutes on days 1, 2, and 3 every 21 days. RESULTS: There was a clinically relevant and statistically significant improvement in overall survival in the TC treatment arm. Median overall survival was 9.4 months (95% confidence interval [CI]:7.9-11.9) in the TC arm, compared to 6.5 months (95% CI:5.8-8.8) with cisplatin alone. The unadjusted hazard ratio for overall survival between treatment arms was 0.76 (95% CI: 0.59-0.98, P = .033) favoring the combination arm. The most common toxicities with TC included myelosuppression, nausea and vomiting, mucositis, rash, and hepatotoxicity. CONCLUSIONS: This report describes the FDA's review supporting this first approval of a chemotherapeutic drug for advanced cervical cancer based on demonstration of a survival benefit.

Approval summary: Docetaxel in combination with prednisone for the treatment of androgen-independent hormone-refractory prostate cancer.

PURPOSE: Docetaxel, a taxane previously approved for the treatment of breast cancer and non-small cell lung cancer, was approved by the United States Food and Drug Administration on May 19, 2004 for use in combination with prednisone for the treatment of metastatic androgen-independent (hormone-refractory) prostate cancer. The purpose of this summary is to review the database supporting this approval. EXPERIMENTAL DESIGN: In a randomized, global study enrolling 1,006 patients, two schedules of docetaxel were compared with mitoxantrone + prednisone as follows: MTZ q 3w, mitoxantrone 12 mg/m2 every 21 days + prednisone 5 mg twice a day for a total of 10 cycles; TXT q 3w, docetaxel 75 mg/m2 every 21 days + prednisone 5 mg twice a day for a total of 10 cycles; and TXT qw, docetaxel 30 mg/m2 days 1, 8, 15, 22, and 29 every 6 weeks + prednisone 5 mg twice a day for a total of 5 cycles. RESULTS: There was a statistically significant overall survival advantage shown for the TXT q 3w arm over MTZ q 3w (median survival 18.9 months versus 16.5 months, P = 0.0094). No overall survival advantage was shown for TXT qw compared with MTZ q 3w. The most commonly occurring adverse events included anemia, neutropenia, infection, nausea, sensory neuropathy, fluid retention, alopecia, nail changes, diarrhea, and fatigue. CONCLUSIONS: This report describes the Food and Drug Administration review supporting this first approval of a combination therapy for hormone-refractory prostate cancer based on demonstration of a survival benefit.

Accelerated approval of oncology products: a decade of experience.

We review the regulatory history of the accelerated approval process and summarize the U.S. Food and Drug Administration experience with accelerated approvals in oncology. The accelerated approval regulations, promulgated in 1992, allow approval of drugs for serious or life-threatening diseases on the basis of a surrogate endpoint that is reasonably likely to predict clinical benefit, such as survival or symptom benefit, pending completion of studies designed to confirm clinical benefit, referred to as phase 4 commitments, which are required to be conducted with due diligence. From 1992 to 2004, 22 applications involving anticancer drugs or biologics were approved. Of these 22 applications, accelerated approval was granted to 15 on the basis of findings from studies without an active comparator (i.e., single-arm studies or studies comparing two dose levels) and to the remaining seven on the basis of one or more randomized studies. Of the 22 approved applications, six (i.e., applications for dexrazoxane, irinotecan, capecitabine, docetaxel, imatinib mesylate, and oxaliplatin) have had one or more indications converted to regular approval. This review reports information that was presented at an Oncologic Drugs Advisory Committee meeting held in March 2003; it also presents a discussion of accelerated approval study designs, the study populations evaluated in the accelerated approval and confirmatory settings, and the integration of accelerated approval into a comprehensive drug development plan.

U.S. Food and Drug Administration drug approval summaries: imatinib mesylate, mesna tablets, and zoledronic acid.

The purpose of this report is to summarize information on drugs recently approved by the U.S. Food and Drug Administration. Three drugs have recently been approved: Gleevec (imatinib mesylate) at a starting dose of 400 or 600 mg daily for the treatment of malignant unresectable and/or metastatic gastrointestinal stromal tumors; Mesnex (mesna) tablets as a prophylactic agent to reduce the incidence of ifosfamide-induced hemorrhagic cystitis, and Zometa (zoledronic acid) for the treatment of patients with multiple myeloma and for patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. The recommended dose and schedule is 4 mg infused over 15 minutes every 3-4 weeks. These three drugs represent three different types of drug approval: Gleevec is an accelerated approval and supplemental new drug application (NDA); Mesnex tablets represent an oral formulation of a drug approved 14 years ago as an intravenous formulation, and Zometa represents a standard NDA for a noncytotoxic, supportive-care drug. Information provided includes rationale for drug development, study design, efficacy and safety results, and pertinent literature references.

Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors.

PURPOSE: Imatinib mesylate (Gleevec; Novartis, East Hanover, NJ)is a receptor tyrosine kinase inhibitor approved previously in 2001 by the United States Food and Drug Administration for the treatment of chronic myelogenous leukemia in blast crisis, accelerated phase, or in chronic phase after failure of IFN-alpha therapy. We review herein the clinical profile of this drug and the regulatory review leading to the approval of a supplemental New Drug Application for the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors (GISTs). EXPERIMENTAL DESIGN: We discuss the efficacy and side effects of imatinib mesylate in a Phase II trial of 147 patients with metastatic and/or unresectable malignant GISTs, the basis for marketing approval, and postmarketing commitments by the drug's manufacturer. RESULTS: Imatinib was assessed in a single, open-label trial involving one European center and three centers in the United States. Seventy-three patients were randomly allocated to receive 400 mg of imatinib daily, and 74 patients received 600 mg daily. At the study report cutoff date, an objective response was confirmed in 56 patients; the overall response rate for the combined study arms was 38% (95% confidence interval, 30-46%). These responses were all partial responses. There was no statistically significant difference in response rates between the two dose groups. Adverse events included edema, fluid retention, nausea, vomiting, diarrhea, myalgias, skin rash, bone marrow suppression, bleeding, and elevations in aspartate aminotransferase, alanine aminotransferase, or bilirubin. Bleeding into the gastrointestinal tract or intratumoral sites occurred in 7 patients (5%) and was not correlated with thrombocytopenia or tumor bulk. The pharmacokinetics of imatinib in GIST patients were similar to those of chronic myelogenous leukemia patients. CONCLUSIONS: On February 1, 2001, imatinib mesylate was approved by the United States Food and Drug Administration for the treatment of malignant metastatic and/or unresectable GISTs. The recommended dose is 400 or 600 mg daily.

Pilot trial of tumor-specific peptide vaccination and continuous infusion interleukin-2 in patients with recurrent Ewing sarcoma and alveolar rhabdomyosarcoma: an inter-institute NIH study.

BACKGROUND: Patients with recurrent Ewing sarcoma and alveolar rhabdomyosarcoma have poor prognoses and limited therapeutic options. We have investigated the use of peptide pulsed vaccination in an attempt to immunologically target the breakpoint region of tumor specific fusion proteins expressed in these tumors. PROCEDURE: Sixteen patients with recurrent, translocation positive, Ewing sarcoma, and alveolar rhabdomyosarcoma underwent apheresis for collection of peripheral blood mononuclear cells. Following countercurrent centrifugal elutriation, an apheresis product comprised predominantly of monocytes but containing small numbers of circulating immature dendritic cells was pulsed with peptides derived from the breakpoint region of the fusion proteins. Vaccines were administered intravenously concomitant with continuous intravenous rhIL-2 at 9 x 10(6) IU/m(2)/day. RESULTS: Toxicity was limited to IL-2 related effects and was generally mild. Following vaccination, all patients showed progressive disease, most in a rapid fashion following the first vaccine. One patient showed evidence of an immunologic response and another showed a mixed clinical response. Patients enrolled on this tumor vaccine trial showed significant immunosuppression and large bulky tumors. CONCLUSIONS: Peptide vaccination as administered in this trial did not alter the dismal clinical outcome for patients with recurrent pediatric sarcomas. Future trials of tumor vaccines in this population should target patient populations with improved immune competence and smaller tumor burdens. Furthermore, optimization of the antigen presenting cell populations may be important for inducing immune responses to peptide antigens.