scholarly journals Assessing Population Diversity in Phase III Trials of Cancer Drugs Supporting FDA Approval in Solid Tumors

2021 ◽  
Author(s):  
Emre Yekedüz ◽  
Dario Trapani ◽  
Wenxin Xu ◽  
Elisabeth GE Vries ◽  
Chris Labaki ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Population Diversity ◽  
Phase Iii ◽  
Cancer Drugs ◽  
Fda Approval ◽  
Phase Iii Trials

scholarly journals Monoclonal Antibodies for the Treatment of Multiple Myeloma: An Update

2018 ◽  
Vol 19 (12) ◽  
pp. 3924 ◽  
Author(s):  
Hanley Abramson
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Checkpoint Inhibitors ◽  
Proteasome Inhibition ◽  
Phase Iii ◽  
Drug Conjugates ◽  
Fda Approval ◽  
Promising Target ◽  
High Death ◽  
Phase Iii Trials

The past two decades have seen a revolution in multiple myeloma (MM) therapy with the introduction of several small molecules, mostly orally effective, whose mechanisms are based on proteasome inhibition, histone deacetylase (HDAC) blockade, and immunomodulation. Immunotherapeutic approaches to MM treatment using monoclonal antibodies (mAbs), while long in development, began to reap success with the identification of CD38 and SLAMF7 as suitable targets for development, culminating in the 2015 Food and Drug Administration (FDA) approval of daratumumab and elotuzumab, respectively. This review highlights additional mAbs now in the developmental pipeline. Isatuximab, another anti-CD38 mAb, currently is under study in four phase III trials and may offer certain advantages over daratumumab. Several antibody-drug conjugates (ADCs) in the early stages of development are described, including JNJ-63723283, which has attained FDA breakthrough status for MM. Other mAbs described in this review include denosumab, recently approved for myeloma-associated bone loss, and checkpoint inhibitors, although the future status of the latter combined with immunomodulators has been clouded by unacceptably high death rates that caused the FDA to issue clinical holds on several of these trials. Also highlighted are the therapies based on the B Cell Maturation Antigen (BCMA), another very promising target for anti-myeloma development.

Efficacy, Safety, and Regulatory Approval of Food and Drug Administration–Designated Breakthrough and Nonbreakthrough Cancer Medicines

2018 ◽  
Vol 36 (18) ◽  
pp. 1805-1812 ◽  
Author(s):  
Thomas J. Hwang ◽  
Jessica M. Franklin ◽  
Christopher T. Chen ◽  
Julie C. Lauffenburger ◽  
Bishal Gyawali ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Drug Administration ◽  
Mechanism Of Action ◽  
Food And Drug Administration ◽  
Progression Free Survival ◽  
Cancer Drugs ◽  
Serious Adverse Events ◽  
Hazard Ratios ◽  
Fda Approval

Purpose The breakthrough therapy program was established in 2012 to expedite the development and review of new medicines. We evaluated the times to approval, efficacy, and safety of breakthrough-designated versus non–breakthrough-designated cancer drugs approved by the US Food and Drug Administration (FDA). Methods We studied all new cancer drugs approved by the FDA between January 2012 and December 2017. Regulatory and therapeutic characteristics (time to FDA approval, pivotal trial efficacy end point, novelty of mechanism of action) were compared between breakthrough-designated and non–breakthrough-designated cancer drugs. Random-effects meta-regression was used to assess the association between breakthrough therapy designation and hazard ratios for progression-free survival (PFS), response rates (RRs) for solid tumors, serious adverse events, and deaths not attributed to disease progression. Results Between 2012 and 2017, the FDA approved 58 new cancer drugs, 25 (43%) of which received breakthrough therapy designation. The median time to first FDA approval was 5.2 years for breakthrough-designated drugs versus 7.1 years for non–breakthrough-designated drugs (difference, 1.9 years; P = .01). There were no statistically significant differences between breakthrough-designated and non–breakthrough-designated drugs in median PFS gains (8.6 v 4.0 months; P = .11), hazard ratios for PFS (0.43 v 0.51; P = .28), or RRs for solid tumors (37% v 39%; P = .74). Breakthrough therapy–designated drugs were not more likely to act via a novel mechanism of action (36% v 39%; P = 1.00). Rates of deaths (6% v 4%; P = .99) and serious adverse events (38% v 36%; P = 0.93) were also similar in breakthrough-designated and non–breakthrough-designated drugs. Conclusion Breakthrough-designated cancer drugs were associated with faster times to approval, but there was no evidence that these drugs provide improvements in safety or novelty; nor was there a statistically significant efficacy advantage when compared with non–breakthrough-designated drugs.

Public Availability of Results of Trials Assessing Cancer Drugs in the United States

2013 ◽  
Vol 31 (24) ◽  
pp. 2998-3003 ◽  
Author(s):  
Thi-Anh-Hoa Nguyen ◽  
Agnes Dechartres ◽  
Soraya Belgherbi ◽  
Philippe Ravaud
Keyword(s):  
United States ◽  
The United States ◽  
Phase Iii ◽  
Cancer Drugs ◽  
Randomized Controlled ◽  
Kaplan Meier ◽  
Phase Iii Trials ◽  
Completion Date ◽  
Public Availability ◽  
Over Time

Purpose To evaluate to what extent results of completed trials of cancer drugs conducted in the United States are publicly available at ClinicalTrials.gov, as required by the Food and Drug Administration Amendments Act (FDAAA), or are published in journals. Methods We searched ClinicalTrials.gov for cancer trials governed by the FDAAA: phase II to IV trials assessing drugs in the United States with a primary completion date between December 26, 2007, and May 31, 2010. For each trial, we also searched PubMed to identify the publication of results. We assessed the cumulative percentages of posted or published results over time by using the Kaplan-Meier method. Results We identified 646 trials, including 209 randomized controlled trials (RCTs). At 12 months after completion of the trials, the cumulative percentages of trials with results posted at ClinicalTrials.gov, published in journals, and available either at ClinicalTrials.gov or in journals were 9% (95% CI, 7% to 11%), 12% (95% CI, 10% to 15%), and 20% (95% CI, 17% to 23%), respectively, and for RCTs, the percentages were 12% (95% CI, 8% to 16%), 5% (95% CI, 2% to 8%), and 17% (95% CI, 12% to 22%), respectively. At 36 months, these percentages were 31% (95% CI, 28% to 35%), 35% (95% CI, 31% to 39%), and 55% (95% CI, 51% to 59%), respectively, and for RCTs, they were 38% (95% CI, 31% to 45%), 32% (95% CI, 25% to 39%), and 56% (95% CI, 48% to 62%), respectively. Public availability of phase III trials was 15% (95% CI, 7% to 23%) at 12 months, 39% (95% CI, 27% to 49%) at 24 months, and 64% (95% CI, 50% to 73%) at 36 months. Conclusion Despite the FDAAA, results for nearly half the trials of cancer drugs in the United States were not publicly available 3 years after completion of the trials.

Recombinant erythropoietin (Epo)/darbepoetin (Darb) associated venous thromboembolism (VTE) in the oncology setting: Findings from the Research on Adverse Drug Events And Reports (RADAR) project

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2552-2552 ◽  
Author(s):  
K. Gleason ◽  
C. Tigue ◽  
P. Yarnold ◽  
J. McKoy ◽  
C. Angelotta ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Adverse Drug Events ◽  
Phase Iii ◽  
Recombinant Erythropoietin ◽  
Two Phase ◽  
Off Label ◽  
Fda Approval ◽  
Increased Risk ◽  
Phase Iii Trials ◽  
Meta Analyses

2552 Background: Cancer patients are at increased risk for VTE as compared to the general population, making VTE as a sADR difficult to detect in the oncology setting. In 2004, two phase III trials identified higher mortality rates among epo-treated cancer patients who were receiving chemotherapy in “off-label” settings- with these studies identifying higher VTE rates in the treatment arms. We reviewed data on epo/darb-associated VTE in the oncology setting. Methods: Data sources were meta-analyses and the FDA’s MedWatch database. Results: Since 1996, only 259 VTE reports (darb: n=30, epo: n=229) of VTE in the setting of chemotherapy and epo/darb were reported to MedWatch. Meta-analyses findings are tabulated below: Conclusions: In 2004, package inserts for Epo/Darb were revised, identifying increased risks of VTE with these agents in the oncology setting. Identification of this adverse drug reaction thirteen years after Epo received FDA approval for this indication (and had been prescribed to > 500,000 cancer patients) illustrates difficulties inherent with current pharmacovigilance efforts. [Table: see text] No significant financial relationships to disclose.

2006 RADAR Report Card on Conversion Rates from Accelerated FDA Approval to Regular FDA Approval for Drugs Used To Treat Hematologic Malignancies: Policy Changes Continue To Be Needed.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3318-3318
Author(s):  
Andrew J. Lurie ◽  
Mark V. Mai ◽  
Martin S. Tallman ◽  
June McCoy ◽  
Charles L. Bennett
Keyword(s):  
Imatinib Mesylate ◽  
Solid Tumors ◽  
Trial Design ◽  
Liposomal Doxorubicin ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Current Status ◽  
Cancer Drugs ◽  
Fda Approval ◽  
Conversion Rates

Abstract Background: At ASH 2004 and 2005, we reported < 20% rates of from accelerated approval (AA) to regular approval (RA) for drugs used to treat hematologic malignancies (HMs). The FDA convened Oncologic Drug Advisory Committee (ODAC) meetings with sponsors of these drugs in 2003 and 2005 outlining recommendations for completion of subpart H trials. Congressmen Markey and Hinchey have raised concern over low rates of completion of subpart H studies for all AA drugs. The Research on Adverse Drug Events and Reports (RADAR) project reviewed the current status of subpart H commitments for all cancer drugs that received AA prior to 2005. Methods: NDAs and supplements for new uses from the FDA, package inserts, and literature reviews were reviewed. Results: Of 19 cancer drugs receiving AA prior to 2005, conversion to RA has occurred for 2 of 9 drugs for HMs and 8 of 11 drugs for solid tumors (STs) (22% vs 73%, p<0.05). Subpart H studies have been ongoing for a median of 5 years for AA drugs for HMs; however, for ST drugs, these studies were completed in a median of 2.5 years. Of 7 subpart H studies reviewed at the 2005 ODAC meeting on AA, subpart H evaluations continue for all 4 for HMs versus 1 of 3 for STs. HMs are characterized by lower rates of target populations, most having > 25,000 newly diagnosed patients annually (25% vs 78%). Recruitment targets are smaller for AA studies for HMs (median, 82 vs 295 patients) and subpart H studies (median, 295 vs 535). Conclusions: Rates of conversion from AA to RA remain poor for drugs for hematologic malignancies but not for solid tumors drugs. In spite of ODAC meetings and two congressional inquiries, little progress ahs been made towards completing these trials. RADAR continues to urge policy makers to modify the AA process for drugs used to treat hematologic malignancies. Hematologic malignancy drugs receiving AA prior to 2005 and current status of subpart studies Drug AA Indication Pts in AA trial design AA year Target # of pts in Subpart H study RA Year Imatinib mesylate CML 1027 2001 1027 2003 Bortezomib MM 202 2003 669 2005 Denileukin difitox* CTCL** 71 1999 195 Pending Liposomal cytarabine* Lymphomatous meningitis** 33 1999 195 Pending Gemtuzumab ozogamicin* AML** 142 2000 342 Pending Alemtuzumab* B-Cell Chronic lymphocytic leukemia** 93 2001 197 Pending Ibritumomab tiuxetan Certain NHLs ** 230 2002 293 Pending Imatinib mesylate CML (pedatrics)** 39 2003 35 Pending Tositumomab Certain NHLs** 60 2003 N/A Pending Solid tumor cancer drugs receiving AA prior to 2005 and current status of subpart studies Drug AA Indication Pts in AA trial design AA year Target # of pts in Subpart H study RA year * Recommendations for completing trials were made at recent ODAC meetings ** Indications with >25,000 new diagnosis annually Irinotecan Colorectal 304 1996 535 1998 Docetaxel Breast 134 1996 326 1998 Capecitabine Breast 163 1998 511 2001 Temozolomide Brain 162 1999 573 2005 Liposomal Doxorubicin* Ovarian 85 1999 474 2005 Oxaliplatin Colorectal 463 2002 795 2004 Anastrozole Breast 9366 2002 6196 2005 Gefitinib Lung 221 2003 1700 2005 Liposomal Doxorubicin* Kaposi’s sarcoma** 77 1995 250 Pending Amifostine Non-small cell lung** 25 1996 366 Withdrawn Imatinib mesylate GI stromal tumors** 147 2002 946 Pending

scholarly journals Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs?

2009 ◽  
Vol 27 (26) ◽  
pp. 4398-4405 ◽  
Author(s):  
Elizabeth A. Richey ◽  
E. Alison Lyons ◽  
Jonathan R. Nebeker ◽  
Veena Shankaran ◽  
June M. McKoy ◽  
...  
Keyword(s):  
Orphan Drug ◽  
Phase Ii ◽  
Phase Iii ◽  
Drug Status ◽  
Cancer Drugs ◽  
Phase Ii Trials ◽  
Development Times ◽  
Phase Iii Trials ◽  
Accelerated Approval ◽  
Confirmatory Trials

Purpose Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. Methods We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. Results Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non–orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non–orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. Conclusion AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.

scholarly journals Trends in pancreatic cancer clinical trials in the United States

2021 ◽  
Vol 9 (11) ◽  
Author(s):  
Lynn Matrisian ◽  
Maren Martinez ◽  
Allison Rosenzweig ◽  
Cassadie Moravek ◽  
Anne-Marie Duliege
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Trials ◽  
The United States ◽  
Phase Iii ◽  
Cancer Type ◽  
Fda Approval ◽  
Treatment Type ◽  
Phase Iii Trials ◽  
Previously Treated Patients ◽  
Previously Treated

Trends in clinical trials for pancreatic cancer between 2011-2020 were tracked in the Pancreatic Cancer Action Network database originally designed to assist in identifying open trials for eligible patients. More than 125 trials specific for pancreatic cancer or including no more than one additional cancer type have been open each year, the majority for patients with a diagnosis of pancreatic adenocarcinoma (PAC). The trends indicate an active and progressive pancreatic cancer research community and include an increasing number of trials for previously treated patients, the emergence of trials for post-adjuvant or maintenance therapy, an increasing number of research-intensive phase 0 trials, increasing seamless phase I/II and II/III trials to improve efficiency, and an increasing number of phase III trials despite historical failures. Trials were analyzed by treatment type and included trials to optimize standard chemotherapy or radiation therapy, trials targeting tumor pathways, the stroma, or the immune system, biomarker-specified trials, and a miscellaneous category of trials testing tumor metabolism, complementary medicine approaches, or alternate energy sources. There was a dramatic increase in immunotherapy trials over this time. Several biomarker-specified trials were initiated, and FDA approval was obtained for biomarker-specified targeted agents, many in a tissue-agnostic setting, indicating an increase in a precision medicine approach to pancreatic cancer treatment. An increasing number of trials tested non-standard approaches, many which progressed to phase III. The trends suggest an encouraging trajectory of pancreatic cancer clinical research.

Do post-approval phase III trials for accelerated approved cancer drugs violate equipoise?

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6026-6026 ◽  
Author(s):  
A. J. Lurie ◽  
B. Djulbegovic ◽  
J. R. Nebeker ◽  
C. Angelotta ◽  
L. I. Gordon ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase Iii ◽  
Necessary Condition ◽  
Marketing Approval ◽  
The Novel ◽  
Cancer Drugs ◽  
Novel Therapy ◽  
Phase Iii Clinical Trials ◽  
Phase Iii Trials ◽  
Accelerated Approval

6026 Background: Since 1992, the Food and Drug Administration (FDA) has allowed accelerated approval of novel cancer drugs based on improvements in surrogate outcomes, provided that subsequent phase III trials, in compliance with subpart H, show evidence of clinical benefits. However, drugs that receive accelerated approval must already show promise, making it difficult to recruit for randomized studies in which patients might get other drugs which are likely to be inferior. We evaluated whether drugs granted accelerated approval were just as likely to be superior as inferior to standard therapy during phase III clinical trials, a necessary condition known as equipoise, which is used as the ethical basis for recruitment. Methods: Descriptions of marketing approval decisions and subpart H commitments for all drugs that received accelerated approval for oncology indications between 1992 and 2005 were obtained from the FDA website, transcripts of the Oncologic Drug Advisory Committee of the FDA, and PubMed searches. Results: Accelerated approval has been granted for 25 drugs and 29 indications. These approvals have been based on phase II clinical trials (23 indications) or phase III trials (6 indications). 14 approvals were for novel cancer therapeutic drugs. Post-approval phase III clinical trials, outlined in subpart H commitments, have been reported for 9 indications associated with common cancers of the colon, lung, or breast, and 1 indication associated with multiple myeloma, a less common cancer, for which 9 studies identified improved clinical outcomes with the accelerated approved drug. Of 15 drugs that received accelerated approval prior to 2003 for cancers that affect small numbers of patients, 13 are years behind planned recruitment milestones for post-approval phase III trials. Conclusion: While the equipoise theory would predict that 50% of the completed phase III trials would support the novel therapy, empirical data have identified that 90% of the studies required by subpart H commitments support the novel therapy. Therefore, it is likely to hinder recruitment to ongoing phase III trials evaluating other accelerated approved cancer drugs. No significant financial relationships to disclose.

Sign in / Sign up

Export Citation Format

Share Document