Accelerated FDA Approval of Drugs Used To Treat Hematologic Malignancies: Are Policy Changes Needed?.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 266-266 ◽  
Author(s):  
Elizabeth A. Lyons ◽  
June M. McKoy ◽  
Steven Belknap ◽  
Kenneth R. Carson ◽  
Charles L. Bennett
Keyword(s):  
Adverse Drug Reactions ◽  
Overall Response Rate ◽  
Response Rate ◽  
Surrogate Endpoint ◽  
Hematologic Malignancies ◽  
Drug Reactions ◽  
Fda Approval ◽  
Post Marketing ◽  
Accelerated Approval ◽  
Full Approval

Abstract Background: In 1992, the FDA extended the accelerated approval program from HIV and AIDs, to include drugs for other diseases that are serious or life-threatening, appear to provide benefit over available therapy, or for which no other therapy is available. Approval is based on a surrogate endpoint, and pharmaceutical companies are required to confirm safety and efficacy by conducting clinical trials with clinically relevant outcomes. Since 1995, eight drugs used to treat hematologic malignancies have received accelerated approval. Methods: Information available to the public under the Freedom of Information Act was surveyed for new drug applications and supplements for new uses approved by the Division of Oncology Products from January 1, 1995 to August 31, 2003. The package insert and corresponding published literature for the approval of each drug were reviewed for indication, time from drug submission to approval, surrogate endpoint, number of patients in trial, percent response and status of full approval. Results: Of the eight drugs which received accelerated FDA approval, approval was granted within 6 months for three (these also received priority review), 1 was approved within 6–12 months; and 4 were approved after 1 year of FDA review. Approvals were based on the surrogate clinical outcome of response rate. Pivotal studies were often small, with < 100 patients (n=3) and 100–250 patients (n=4). The overall response rate was < 33% for four drugs. Only one of the approvals has been converted to full approval (imatinib). Post-marketing studies have identified three potentially fatal adverse drug reactions related to two drugs (gemtuzumab associated veno-occlusive diesease, gemtuzumab associated severe infusion reactions and imatinib associated upper GI bleeds). Conclusion: To date, accelerated FDA approval for eight hematologic oncology drugs has been granted based on pivotal trials with small sample sizes and low response rates (with the exception of imatinib). Conversion to full approval has rarely occurred (N=1) and post-marketing identification of severe adverse drug reactions, in what were initially off-label settings, has occurred for two of the drugs. Modification of the accelerated approval process for hematologic oncology drugs should be considered. FDA approval information for accelerated approval drugs used to treat hematologic malignancies. Drug Name Indication Time to Approval (Months) N in Trial Overall Response Rate (%) Alemtuzumab CLL 16.5 93 33 Bortezomib Myeloma 3.7 188 14 Cytarabine liposomal Lymphomatous meningitis 5.5 17 41 Denileukin diftitox T-cell lymphoma 14 206 16 Gemtuzumab CD33 positive AML 7 142 26 Ibritumomab tiuxetan Low-grade NHL 15.6 157 62 Imatinib mesylate CML 3 1027 66 Tositumomab NHL 48 40 63

Alert systems for post-marketing surveillance of adverse drug reactions

1993 ◽  
Vol 12 (24) ◽  
pp. 2383-2393 ◽  
Author(s):  
Michaela Praus ◽  
Fritz Schindel ◽  
Reinhard Fescharek ◽  
Sabine Schwarz
Keyword(s):  
Adverse Drug Reactions ◽  
Drug Reactions ◽  
Post Marketing Surveillance ◽  
Post Marketing

Differences in safety profiles of newly approved medications for multiple myeloma in real-world settings versus randomized controlled trials

2020 ◽  
pp. 107815522094193
Author(s):  
Eric P Borrelli ◽  
Conor G McGladrigan
Keyword(s):  
Multiple Myeloma ◽  
Randomized Controlled Trials ◽  
Adverse Drug Reactions ◽  
Malignant Neoplasm ◽  
Controlled Trials ◽  
Site Reaction ◽  
Drug Reactions ◽  
Infusion Site ◽  
Randomized Controlled ◽  
Fda Approval

Background Four new agents (elotuzumab, ixazomib, panobinostat, and daratumumab) were approved by the US Food and Drug Administration (FDA) in 2015 for the treatment of multiple myeloma. Our objective was to compare the safety profiles of these new medications in real-world settings and their randomized controlled trial(s). Material and methods An analysis was conducted of the FDA Adverse Event Reporting System (FAERS) for each drug consisting of the quarter that the drug received its FDA approval and the eight subsequent quarters. Reporting odds ratios and corresponding 95% confidence intervals were then calculated for each drug for each of the 10 most frequent adverse drug reactions. The randomized controlled trials that led to initial FDA approval for these medications were subsequently reviewed to assess the 10 most frequently reported adverse drug reactions in these trials. Results There were only two adverse drug reactions in the top 10 of both FAERS and its randomized controlled trials for elotuzumab (anaemia, diarrhoea) and for daratumumab (cough, back pain), five for ixazomib (diarrhoea, constipation, fatigue, nausea, peripheral neuropathy), and four panobinostat (diarrhoea, fatigue, nausea, constipation). Ixazomib had two adverse drug reactions with a significant reporting odds ratios greater than a 10-fold increased risk (plasma cell myeloma, peripheral neuropathy); elotuzumab had three adverse drug reactions (infusion site reaction, malignant neoplasm progression, deep vein thrombosis); daratumumab had three adverse drug reactions (infusion site reaction, bronchospasm, chills), while panobinostat had four (malignant neoplasm progression, decreased platelet count, diarrhoea, increased blood creatinine). Conclusion This analysis helps to highlight the importance of conducting postmarketing pharmacovigilance studies to better understand the potential adverse reactions of these medications.

Incidence of Roentgen Contrast Medium Reactions after Intravenous Injection in Pre-Registration Trials and Post-Marketing Surveillances

1993 ◽  
Vol 34 (3) ◽  
pp. 210-213 ◽  
Author(s):  
E. Andrew ◽  
T. Haider
Keyword(s):  
Relative Risk ◽  
Adverse Drug Reactions ◽  
Odds Ratio ◽  
Adverse Reactions ◽  
Drug Reactions ◽  
Feasible Method ◽  
Ionic Contrast ◽  
Different Types ◽  
Post Marketing ◽  
The Absolute

The relative risk of adverse drug reactions of ionic versus non-ionic contrast media injected i.v. were compared for different types of trials using odds-ratio. The absolute and relative risk found in large post-marketing trials were compared with that found in the iohexol pre-registration trials. The absolute risks were 2 to 10 times higher in the pre-registration trials compared to the post-marketing surveillances. The relative risk for all adverse drug reactions was 3 to 6 times higher for ionic vs. non-ionic media and independent of pre- or post-registration studies. The odds-ratio seems to be a feasible method of comparing the relative risk of adverse reactions in various trials.

scholarly journals Characteristics of adverse drug reactions in a vemurafenib early post-marketing phase vigilance study in Japan

2017 ◽  
Vol 20 (2) ◽  
pp. 169-175 ◽  
Author(s):  
H. Uhara ◽  
Y. Kiyohara ◽  
A. Tsuda ◽  
M. Takata ◽  
N. Yamazaki
Keyword(s):  
Adverse Drug Reactions ◽  
Drug Reactions ◽  
Post Marketing

The final report of post-marketing surveillance for cetuximab in colorectal cancer in Japan.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 590-590 ◽  
Author(s):  
K. Yamaguchi ◽  
T. Satoh ◽  
T. Watanabe ◽  
M. Ishiguro ◽  
K. Maruyama ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Drug Reactions ◽  
Infusion Reaction ◽  
Gastrointestinal Disorders ◽  
Final Report ◽  
Skin Disorders ◽  
Drug Reactions ◽  
Post Marketing Surveillance ◽  
Number Of Patients ◽  
Post Marketing

590 Background: Cetuximab (ERBITUX) was approved in Jul 2008 in Japan with indication for EGFR-positive and unresectable metastatic or refractory colorectal cancer. Post-marketing surveillance is required by Japanese Health Authority to collect, obtain, verify or validate information on the safety, efficacy and quality of medicines. We conducted this surveillance in all patients treated with cetuximab to access in practical use since clinical data on Japanese patients are limited. Methods: The target number of patients was 1,800. Following adverse drug reactions were investigated: infusion reaction, skin disorders, interstitial lung diseases, electrolyte abnormalities (including hypomagnesemia), heart toxicities, gastrointestinal disorders, thrombosis/embolism, delayed wound healing, and eye disorders. Results: Between Sep 2008 until Jan 2010, 2,126 pts registered, 2,006 pts were evaluable for safety (safety population), 1,687 pts for efficacy (efficacy population). Of the 2,006 pts, 1,975 pts (98.5%) were EGFR-positive. Patients characteristics: male/female; 1,234/772 (61.5%/38.5%), median age; 64 (range 18-87), site of primary tumor; colon/rectal/others (multiple selection); 1,235/775/3 (61.6%/38.6%/0.2%), PS0/PS1; 1,370/630 (68.3%/31.4%), combination chemotherapy; cetuximab monotherapy/CPT-11/FOLFIRI: 460/1,255/256 (22.9%/62.56%/12.8%). Of the 2,006 pts, 133 pts (6.6%) and 1,869 pts (93.2%) were treated in second-line and in third-line or later treatment, respectively. The adverse drug reactions incidence was 89.9%. Incidence of skin disorders, gastrointestinal disorders, electrolyte abnormality including hypomagnesaemia, and infusion reaction were 83.7%, 23.1%, 11.5%, and 5.7%, respectively. Efficacy result: Of the 1,687 pts, 658 pts (39.0%) were evaluated to be effective. Of the 658 pts, 614 pts (93.3%) experienced skin adverse reactions. Conclusions: This post-marketing surveillance confirms the safety and efficacy of cetuximab in the Japanese population treated in clinical practice. The outcome of this surveillance with Japanese 2,006 pts would be useful for clinical use of cetuximab. [Table: see text]

scholarly journals A Multi-Agent System for Reporting Suspected Adverse Drug Reactions

2014 ◽  
Vol 6 (3) ◽  
Author(s):  
Yanqing Ji ◽  
Fangyang Shen ◽  
See-Yan Lau ◽  
John Tran
Keyword(s):  
Adverse Drug Reactions ◽  
Healthcare Professionals ◽  
Public Health Problem ◽  
Reporting Rate ◽  
Drug Reactions ◽  
Data Mining Approach ◽  
Spontaneous Reports ◽  
Post Marketing ◽  
Multi Agent ◽  
Suspected Adverse Drug Reactions

Adverse drug reactions (ADRs) represent a serious worldwide public health problem. Current post-marketing ADR detection approaches largely rely on spontaneous reports filed by various healthcare professionals such as physicians, pharmacists et.al.. Underreporting is a serious deficiency of these methods - the actually reported adverse events represent less than 10% of all cases. Studies show that two important reasons that cause the underreporting are: 1) healthcare professionals are unaware of encountered ADRs, especially for those unusual ADRs; 2) they are too busy to voluntarily report ADRs since it takes a lot of time to fill out the reporting forms. This paper addresses these two issues by developing a multi-agent ADR reporting system. The system 1) helps healthcare professionals detect the potential causal relationship between a drug and an ADR by analyzing patients’ electronic records via both case-based analysis and statistical data mining approach; 2) allows healthcare professionals to add new rules to signal potential ADRs based on their medical expertise; 3) makes the reporting much easier by automatically linking the patients’ electronic data with the reporting form. A functioning prototype of the system has been developed. The proposed data analysis approaches as well as the performance of the system have been tested. The results indicate that this system has a great potential to improve the spontaneous reporting rate of suspected adverse drug reactions.

scholarly journals An analysis of the pattern and profile of adverse drug reactions reported at a tertiary care teaching hospital in Kerala, India: a retrospective record based observational study

2018 ◽  
Vol 7 (9) ◽  
pp. 1715
Author(s):  
Abdul Aslam P. ◽  
Sangeetha Purushothaman ◽  
Jihana Shajahan
Keyword(s):  
Adverse Drug Reactions ◽  
Tertiary Care ◽  
Care Hospital ◽  
Drug Reactions ◽  
Cross Sectional ◽  
Important Concern ◽  
Post Marketing ◽  
The Individual ◽  
Prolonged Hospital ◽  
Sectional Analysis

Background: Adverse drug reactions (ADRs) are an important concern in modern therapeutics. Due to limitations in identifying ADRs during research phase, organized post marketing studies are essential. However, there are only few recent studies on this subject available in India. Hence this study was done in a tertiary care hospital in South Kerala to evaluate the profile and causality of ADRs.Methods: The details of patients who developed ADRs during the period from October 2016 to November 2017 were collected. Data collection was done using the suspected drug reactions monitoring form by CDSCO used under PvPI and a retrospective observational cross-sectional analysis was done. The profile and causality of ADRs were evaluated.Results: The total number of ADR events reported was 300. 179 ADRs were hypersensitivity reactions (Aronson Type B) and the remaining 121 reactions were Type A reactions. The individual drug class causing majority of the ADRs was antibiotics (36%). Commonest significant dose related ADR was bleeding (7%) caused by combined use of antiplatelets and anticoagulants. The organ system most affected as per SOC classification was skin and appendages (56%). Causality assessment revealed that majority (76%) belonged to “probable” category, whereas 23.6% were of “possible” type.Conclusions: The development of ADRs can significantly affect treatment course – interruption of drug therapy, use of additional drugs and prolonged hospital stay. Employing monitors dedicated to ADR detection and education of prescribers to closely monitor patients can help manage ADRs effectively.

scholarly journals Safety and effectiveness of bevacizumab in Japanese patients with malignant glioma: a post-marketing surveillance study

2019 ◽  
Vol 49 (11) ◽  
pp. 1016-1023 ◽  
Author(s):  
Nagane Motoo ◽  
Yasuko Hayashi ◽  
Ayaka Shimizu ◽  
Masako Ura ◽  
Ryo Nishikawa
Keyword(s):  
Overall Survival ◽  
Survival Rate ◽  
Malignant Glioma ◽  
Adverse Drug Reactions ◽  
Median Overall Survival ◽  
Surveillance Study ◽  
Newly Diagnosed ◽  
Drug Reactions ◽  
Post Marketing Surveillance ◽  
Post Marketing

Abstract Objective This surveillance study was conducted to verify the post-market safety and effectiveness of bevacizumab, which was approved in Japan in 2013 for the treatment of patients with newly diagnosed and or recurrent malignant glioma. Methods This was a prospective, observational, multicenter post-marketing surveillance study. Patients with newly diagnosed or recurrent malignant glioma scheduled for bevacizumab treatment were enrolled. The incidence and severity of adverse drug reactions were calculated. The effectiveness of bevacizumab was assessed by the 1-year survival rate and the overall survival rate. Results The safety analysis set and the effectiveness analysis set each comprised 258 of the 268 enrolled patients: tumours were newly diagnosed in 80 patients (31%) and recurrent in 178 patients (68.9%). The incidence of grade ≥ 3 adverse drug reactions was 15.1%. Adverse drug reactions of special interest included 14 cerebral bleeding events and 11 infections. Of the 80 patients with newly diagnosed malignant glioma, 44 (55%) were alive throughout the 18-month observation period. The 1-year survival rate for patients with newly diagnosed glioblastoma was 78%. Median overall survival was not calculated, but 51.2% of patients were alive at the last date of observation of the last observed patient. In patients with recurrent glioblastoma, the 1-year survival rate was 38.9%, and the median overall survival was 10.2 months. Conclusions The results suggest no new safety concerns, and the effectiveness might be similar to previously reported data in clinical trials. Therefore, bevacizumab is considered as one of the treatment options for patients with malignant glioma in real-world clinical practice.

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