Summary
Major discrepancies concerning risk-benefit assessments and regulatory actions are frequent among regulatory agencies. We explored the differences by scrutinizing a case of gemtuzumab ozogamicin (GO) in patients with acute myeloid leukaemia (AML). Assessment reports of GO were retrieved form the websites of the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and Japanese regulatory agency, and we also reviewed published clinical trials. While GO was approved by the US FDA under the accelerated approval program in 2000, it was withdrawn from the market in 2010, based on the required post-marketing commitment failure. The EMA refused granting marketing authorization for GO in 2008 on the grounds that there were no randomised controlled trials (RCTs). GO was approved as an orphan drug in Japan in 2005, and the Japanese regulatory authority decided to continue with the approval in 2010 on the condition that post-marketing surveillance is strengthened. Under these situations, promising new results of RCTs appeared in 2011, and the role of GO in AML treatment was refocused worldwide. The stringent regulation may not be suitable in case of an orphan drug of targeted therapy, and more room should be kept to facilitate effective developments of new anti-neoplastic agents.
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References
Goozner M (2010) FDA increases focus on postmarketing studies. J Natl Cancer Inst 102(17):1302–1304
Young RC (2010) Cancer clinical trials—a chronic but curable crisis. N Engl J Med 363(4):306–309
Richey EA, Lyons EA, Nebeker JR et al (2009) Accelerated approval of cancer drugs: improved access to therapeutic breakthroughs or early release of unsafe and ineffective drugs? J Clin Oncol 27(26):4398–4405
Boon WP, Moors EH, Meijer A, Schellekens H (2010) Conditional approval and approval under exceptional circumstances as regulatory instruments for stimulating responsible drug innovation in Europe. Clin Pharmacol Ther 88(6):848–853
Shibuya K, Hashimoto H, Ikegami N et al (2011) Future of Japan’s system of good health at low cost with equity: beyond universal coverage. Lancet 378(9798):1265–1273
Walter RB, Appelbaum FR, Estey EH, Bernstein ID (2012) Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood 119(26):6198–208
The US Food and Drug Administration. Drug Approvals and Databases, Mylotarg (gemtuzumab ozogamicin) Injection. [accessed May 30, 2012]; Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21174_Mylotorg.cfm
The European Medicines Agency. European public assessment reports, Mylotarg. [accessed May 30, 2012]; Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000705/human_med_000915.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d125&jsenabled=false
Pharmaceutical and Medicines Agency. Drug Approvals and Databases, Mylotarg Injection. [accessed May 30, 2012]; Available from: http://www.info.pmda.go.jp/shinyaku/P200500021/53039600_21700AMY00219_Q100_3.pdf
The US Food and Drug Administration. Pfizer Voluntarily Withdraws Cancer Treatment Mylotarg from U.S. Market. [accessed May 30, 2012]; Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm216448.htm
Pharmaceutical and Medicines Agency. Assessment report, Mylotarg. [accessed May 30, 2012]; Available from: http://www.pmda.go.jp/english/service/pdf/precautions/PMDSI-277.pdf
Sievers EL, Larson RA, Stadtmauer EA et al (2001) Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 19(13):3244–3254
Petersdorf S, Kopecky K, Stuart RK et al (2009) Preliminary results of Southwest Oncology Group Study S0106: An international intergroup phase 3 randomized trial comparing the addition of gemtuzumab ozogamicin to standard induction therapy versus standard induction therapy followed by a second randomization to post-consolidation gemtuzumab ozogamicin versus no additional therapy for previously untreated acute myeloid leukemia. Blood (ASH Annual Meeting Abstracts) 114:790
Burnett AK, Hills RK, Milligan D et al (2011) Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol 29(4):369–377
Kobayashi Y, Tobinai K, Takeshita A et al. Phase I/II study of humanized anti-CD33 antibody conjugated with calicheamicin, gemtuzumab ozogamicin, in relapsed or refractory acute myeloid leukemia: final results of Japanese multicenter cooperative study. Int J Hematol;89(4):460–469
Announcement of the Japanese Society of Medical Oncology. On the Registration System of Mylotarg. [accessed May 30, 2012]; Available from: http://www.jsmo.or.jp/news/jsmo/20110810.html
Castaigne S, Pautas C, Terre C et al (2011) Fractionated doses of Gemtuzumab Ozogamicin (GO) combined to standard chemotherapy (CT) improve event-free and overall survival in newly-diagnosed de novo AML patients aged 50–70 years old: a prospective randomized phase 3 trial from the Acute Leukemia French Association (ALFA). Blood (ASH Annual Meeting Abstracts) 118:6
Castaigne S, Pautas C, Terre C et al (2012) Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 379:1508–1516
Burnett AK, Hills RK, Hunter A et al (2011) The addition of gemtuzumab ozogamicin to intensive chemotherapy in older patients with AML produces a significant improvement in overall survival: results of the UK NCRI AML16 randomized trial. Blood (ASH Annual Meeting Abstracts) 118:582
Lo-Coco F, Cimino G, Breccia M et al (2004) Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 104(7):1995–1999
Breccia M, Cimino G, Diverio D et al (2007) Sustained molecular remission after low dose gemtuzumab-ozogamicin in elderly patients with advanced acute promyelocytic leukemia. Haematologica 92(9):1273–1274
Chevallier P, Delaunay J, Turlure P et al (2008) Long-term disease-free survival after gemtuzumab, intermediate-dose cytarabine, and mitoxantrone in patients with CD33(+) primary resistant or relapsed acute myeloid leukemia. J Clin Oncol 26(32):5192–5197
Taksin AL, Legrand O, Raffoux E et al (2007) High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group. Leukemia 21(1):66–71
Lowenberg B, Pabst T, Vellenga E et al (2011) Cytarabine dose for acute myeloid leukemia. N Engl J Med 364(11):1027–1036
Clarke WT, Marks PW (2010) Gemtuzumab ozogamicin: is there room for salvage? Blood 116:2618–2619
Kell WJ, Burnett AK, Chopra R et al (2003) A feasibility study of simultaneous administration of gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in younger patients with acute myeloid leukemia. Blood 102:4277–4283
Amadori S, Suciu S, Willemze R et al (2004) Sequential administration of gemtuzumab ozogamicin and conventional chemotherapy as first line therapy in elderly patients with acute myeloid leukemia: a phase II study (AML-15) of the EORTC and GIMEMA leukemia groups. Haematologica 89:950–956
Larson RA, Sievers EL, Stadtmauer EA et al (2005) Final report of the efficacy and safety of gemtuzumab onogamicine (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer 104:1442–1452
Amadori S, Suciu S, Stasi R et al (2005) Gemtuzumab Ozogamicin (Mylotarg) as single-agent treatment for frail patients 61 years of age and older with acute myeloid leukemia: final results of AML-15B, a phase 2 study of the European Organisation for Research and Treatment of Cancer and Gruppo Italiano Malattie Ematologiche dell’Adulto Leukemia Groups. Leukemia 19:1768–1773
Lowenberg B, Beck J, Graux C et al (2010) Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study. Blood 115:2586–2591
Fernandez HF, Sun Z, Litzow MR et al (2011) Autologous transplantation gives encouraging results for young adults with favorable-risk acute myeloid leukemia, but is not improved with gemtuzumab ozogamicin. Blood 117:5306–5313
Brunnberg U, Mohr M, Noppeney R et al (2012) Induction therapy of AML with ara-C plus daunorubicin versus ara-C plus gemtuzumab ozogamicin: a randomized phase II trial in elderly patients. Ann Oncol 23:990–996
Tanimoto T, Kusumi E, Ono S (2012) Regulatory review of novel therapeutics. N Engl J Med
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Tanimoto, T., Tsubokura, M., Mori, J. et al. Differences in drug approval processes of 3 regulatory agencies: a case study of gemtuzumab ozogamicin. Invest New Drugs 31, 473–478 (2013). https://doi.org/10.1007/s10637-012-9877-8
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DOI: https://doi.org/10.1007/s10637-012-9877-8