scholarly journals Reimbursement recommendations for cancer drugs supported by phase II evidence in Canada

2020 ◽  
Vol 27 (5) ◽  
Author(s):  
Y.Y.R. Li ◽  
H. Mai ◽  
M.E. Trudeau ◽  
N. Mittmann ◽  
K. Chiasson ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Benefit ◽  
Multivariable Analysis ◽  
Unmet Need ◽  
Phase Iii ◽  
Expert Review ◽  
Phase Iii Study ◽  
Patient Values ◽  
Background Phase ◽  
Positive Recommendation

Background Phase ii data are increasingly being used as primary evidence for public reimbursement for oncologic drugs. We compared the frequency of reimbursement recommendations for phase ii and phase iii submissions and assessed for variables associated with a positive or conditional recommendation. Methods We identified submissions made to the pan-Canadian Oncology Drug Review’s Expert Review Commit­tee (perc), of the Canadian Agency for Drugs and Technologies in Health, July 2011 to July 2019, that were supported only by phase ii data. We identified variables within the perc’s deliberative framework, including clinical and eco­nomic factors, associated with the final reimbursement recommendation. We conducted a multivariable analysis with logistic regression for these variables: feasibility of phase iii study, hematologic indication, and unmet need. Results We identified 139 submissions with a perc final recommendation. In 27 instances (19%), the submission had only phase ii evidence, and a positive recommendation was issued for 63% of them (the positive recommendation rate was 82% for submissions with phase iii evidence). Clinical benefit (p < 0.001), unmet need (p = 0.047), and patient alignment (p = 0.015) were associated with a positive recommendation. If a future phase iii study was deemed feasible for submissions with only phase ii evidence, then in univariable (p = 0.040) and multivariable analysis (p = 0.024), the perc was less likely to recommend reimbursement (odds ratio: 0.132). Conclusions Although more than half the oncologic submissions with phase ii data were recommended for pub­lic reimbursement, compared with submissions having phase iii data, they were less likely to be recommended. A positive or conditional recommendation was more likely if clinical benefit and alignment with patient values was demonstrated. The perc was less likely to recommend reimbursement for submissions with phase ii evidence if a phase iii trial was deemed possible.

Reimbursement recommendations for cancer drugs supported by phase II evidence in Canada.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14133-e14133
Author(s):  
Regina Li ◽  
Helen Mai ◽  
Kaitlyn Chiasson ◽  
Maureen E. Trudeau ◽  
Kelvin K. Chan ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Benefit ◽  
Multivariable Analysis ◽  
Unmet Need ◽  
Current Treatment ◽  
Phase Iii ◽  
Treatment Standards ◽  
Exact Test ◽  
Phase Iii Study ◽  
Positive Recommendation

e14133 Background: Historically, pharmaceutical companies submitted phase III evidence for consideration of public reimbursement; however, phase II data is being more commonly used as primary evidence. Whether submissions with phase II data lead to similar rates of positive reimbursement recommendations as phase III data has not been comprehensively investigated. We compared frequency of reimbursement recommendations between phase II and phase III submissions for oncologic drugs and assessed for factors associated with a positive or conditional recommendation. Methods: We identified all submissions with phase II data from the CADTH pCODR’s expert review committee (pERC) recommendations from July 2011 to July 2019. We identified fourteen binary variables relating to clinical benefit, patient-based values, economic impact, and adoption feasibility. We used Fisher’s exact test to characterize associations between all variables and the final recommendation. We conducted multivariable analysis with logistic regression for three variables: feasibility of phase III study, hematologic indication, and unmet need. Results: We identified 139 submissions with a pERC final recommendation. Twenty-seven (19%) submissions were supported by phase II evidence, with 63% having a positive recommendation in comparison to 82% among submissions with phase III evidence. Clinical benefit (p < 0.001), gap in current treatment standards (p = 0.047), and patient alignment (p = 0.015) were associated with a positive recommendation, whereas the future feasibility of conducting a phase III study was associated with a negative recommendation (p = 0.040). No significant association was found between the recommendation and factors related to cost effectiveness or adoption feasibility. In multivariable analysis, only feasibility of a phase III study was significantly associated with a negative recommendation (p = 0.024, OR = 0.132). Conclusions: Oncologic submissions with phase II data were less likely to be recommended for public reimbursement than phase III studies. Positive or conditional recommendation was more likely if they demonstrated clinical benefit and aligned with patient values. pERC was less likely to recommend a submission with phase II if a phase III trial was either possible or already initiated.

Phase II testing of melphalan in children with newly diagnosed rhabdomyosarcoma: a model for anticancer drug development.

1988 ◽  
Vol 6 (2) ◽  
pp. 308-314 ◽  
Author(s):  
M E Horowitz ◽  
E Etcubanas ◽  
M L Christensen ◽  
J A Houghton ◽  
S L George ◽  
...  
Keyword(s):  
Phase Ii ◽  
Drug Disposition ◽  
Clinical Performance ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Heavily Pretreated ◽  
Phase Iii Study ◽  
Successful Testing ◽  
Previously Treated Patients ◽  
Pretreated Patients

We describe events that led to successful testing of melphalan, one of the nitrogen mustard compounds, in children with newly diagnosed, poor-risk rhabdomyosarcoma (RMS). Preclinical studies with xenografts of human RMS, growing in the flanks of immune-deprived mice, had indicated superior oncolytic activity by melphalan compared with other agents commonly used to treat this tumor. However, in a conventional phase II trial, melphalan failed to produce partial responses in 12 of 13 heavily pretreated patients with recurrent tumors. Subsequent comparison of the drug's pharmacokinetics in mice and patients indicated that its poor clinical performance was not the result of interspecies differences in drug disposition. Therefore, we elected to retest melphalan in untreated patients, before they were enrolled in a phase III study. Of 13 children who received the drug for 6 weeks, ten had partial responses, confirming the significant antitumor activity seen in the xenograft system. These findings illustrate the inherent limitations of phase II drug trials in previously treated patients and suggest a useful paradigm for the development of antineoplastic drugs.

scholarly journals The clinical benefit of ruxolitinib across patient subgroups: analysis of a placebo-controlled, Phase III study in patients with myelofibrosis

2013 ◽  
Vol 161 (4) ◽  
pp. 508-516 ◽  
Author(s):  
Srdan Verstovsek ◽  
Ruben A. Mesa ◽  
Jason Gotlib ◽  
Richard S. Levy ◽  
Vikas Gupta ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Phase Iii ◽  
Phase Iii Study ◽  
Patient Subgroups

Randomized Multicenter Phase II Trial of a Biweekly Regimen of Fluorouracil and Leucovorin (LV5FU2), LV5FU2 Plus Cisplatin, or LV5FU2 Plus Irinotecan in Patients With Previously Untreated Metastatic Gastric Cancer: A Fédération Francophone de Cancérologie Digestive Group Study—FFCD 9803

2004 ◽  
Vol 22 (21) ◽  
pp. 4319-4328 ◽  
Author(s):  
Olivier Bouché ◽  
Jean Luc Raoul ◽  
Franck Bonnetain ◽  
Marc Giovannini ◽  
Pierre Luc Etienne ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Phase Iii ◽  
Survival Times ◽  
Multicenter Phase ◽  
Independent Expert ◽  
Phase Iii Study ◽  
Cancérologie Digestive

Purpose To determine the efficacy and safety of a biweekly regimen of leucovorin (LV) plus fluorouracil (FU) alone or in combination with cisplatin or irinotecan in patients with previously untreated metastatic gastric adenocarcinoma and to select the best arm for a phase III study. Patients and Methods One hundred thirty-six patients (two were ineligible) were enrolled onto the randomized multicenter phase II trial. Patients received LV 200 mg/m2 (2-hour infusion) followed by FU 400 mg/m2 (bolus) and FU 600 mg/m2 (22-hour continuous infusion) on days 1 and 2 every 14 days (LV5FU2; arm A), LV5FU2 plus cisplatin 50 mg/m2 (1-hour infusion) on day 1 or 2 (arm B), or LV5FU2 plus irinotecan 180 mg/m2 (2-hour infusion) on day 1 (arm C). Results The overall response rates, which were confirmed by an independent expert panel, were 13% (95% CI, 3.4% to 23.3%), 27% (95% CI, 14.1% to 40.4%), and 40% (95% CI, 25.7% to 54.3%) for arms A, B, and C, respectively. Median progression-free survival and overall survival times were 3.2 months (95% CI, 1.8 to 4.6 months) and 6.8 months (95% CI, 2.6 to 11.1 months) with LV5FU2, respectively; 4.9 months (95% CI, 3.5 to 6.3 months) and 9.5 months (95% CI, 6.9 to 12.2 months) with LV5FU2-cisplatin, respectively; and 6.9 months (95% CI, 5.5 to 8.3 months) and 11.3 months (95% CI, 9.3 to 13.3 months) with LV5FU2-irinotecan, respectively. Conclusion Of the three regimens tested, the combination of LV5FU2-irinotecan is the most promising and will be assessed in a phase III trial.

scholarly journals MICS-Asia III: Overview of model inter-comparison and evaluation of acid deposition over Asia

2019 ◽  
Author(s):  
Syuichi Itahashi ◽  
Baozhu Ge ◽  
Keiichi Sato ◽  
Joshua S. Fu ◽  
Xuemei Wang ◽  
...  
Keyword(s):  
Acid Deposition ◽  
Phase Ii ◽  
Wet Deposition ◽  
Lessons Learned ◽  
Phase Iii ◽  
Anthropogenic Emissions ◽  
Observation Data ◽  
Total Deposition ◽  
North Asia ◽  
Phase Iii Study

Abstract. The Model Inter-Comparison Study for Asia (MICS-Asia) Phase III was conducted to promote understanding of regional air quality and climate change in Asia, which have received growing attention due to the huge amount of anthropogenic emissions worldwide. This study provides an overview of acid depositions. Specifically, dry and wet depositions of the following species were analyzed: S (sulfate aerosol, sulfur dioxide (SO2), and sulfuric acid (H2SO4)), N (nitrate aerosol, nitrogen monoxide (NO), nitrogen dioxide (NO2), and nitric acid (HNO3)), and A (ammonium aerosol and ammonia (NH3)). The wet deposition simulated by a total of nine models was analyzed and evaluated using ground observation data from the Acid Deposition Monitoring Network in East Asia (EANET). In this Phase III study, the number of observation sites was increased to 54 from 37 in the Phase II study, and Southeast Asian countries were newly added. Additionally, whereas the analysis period was limited to representative months of each season in MICS-Asia Phase II, this Phase III study analyzed the full year of 2010. The scope of this overview mainly focuses on the annual accumulated depositions. In general, models can capture the observed wet depositions over Asia but underestimate the wet deposition of S and A and show large differences in the wet deposition of N. Furthermore, the ratio of wet deposition to the total deposition (the sum of dry and wet deposition) was investigated in order to understand the role of important processes in the total deposition. The general dominance of wet deposition over Asia and attributions from dry deposition over land were consistently found in all models. Then, total deposition maps over 13 countries participating in EANET were produced, and the balance between deposition and anthropogenic emissions was calculated. Excesses of deposition, rather than of anthropogenic emissions, were found over Japan, North Asia, and Southeast Asia, indicating the possibility of long-range transport within and outside Asia, as well as other emission sources. To improve the ability of models to capture the observed wet deposition, two approaches were attempted, namely, ensemble and precipitation adjustment. The ensemble approach was effective at modulating the differences in performance among models, and the precipitation-adjusted approach demonstrated that the model performance for precipitation played a key role in better simulating wet deposition. Finally, the lessons learned from this Phase III study and future perspectives for Phase IV are summarized.

“Getting to go” for FDA Approvals for the Treatment of Hematologic Versus Solid Tumor Malignancies: A Report from the Research on Adverse Drug Events and Reports (RADAR) Project

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2402-2402
Author(s):  
Elizabeth A Richey ◽  
Veena Shankaran ◽  
Steven Hirschfeld ◽  
Steven M Trifilio ◽  
June McKoy ◽  
...  
Keyword(s):  
Phase Ii ◽  
Solid Tumor ◽  
Clinical Benefit ◽  
Hematologic Malignancy ◽  
Hematologic Malignancies ◽  
Black Box ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Development Times ◽  
Black Box Warnings

Abstract Background: The accelerated approval (AA) regulation (21CFR314.510 Subpart H) is granted by the Food and Drug Administration (FDA) when drugs for serious medical illnesses are shown to be an improvement over available therapy. AA provides an option to use surrogate outcomes considered likely to predict clinical benefit. AA was initially developed to hasten access to HIV drugs, then, in 1995, AA was extended to cancer indications. Sponsors receiving AA are required to confirm clinical benefit (termed subpart H trials). Policy makers have several raised concerns: AA is no longer relevant today as the approval bar via this mechanism has been raised too high; many drugs that received AA did not complete subpart H trials; and some drugs approved by AA were subsequently found to be unsafe or ineffective. Methods: Using publicly available databases, we compared safety, efficacy, clinical development times, and subpart H completion rates for FDA-approved new molecular entities (NMEs) for hematologic and solid tumor cancers from 1995–2008. Results: 37% of all oncology NMEs received AA versus regular approval (64% during 1995–2003 and 33% during 2004–2008). Twenty oncology NMEs received FDA approval for hematologic malignancies (lymphomas, leukemias, Kaposi’s sarcoma, and myelodysplastic syndromes), accounting for 34% of regular approvals and 53% of AAs for oncology NMEs. Compared to NMEs approved for solid tumors, NMEs approved for hematologic malignancies were more likely to involve Orphan Drug indications (95% vs. 32%); to have shorter development times, defined as the interval between investigational new drug filing and marketing approval, (median 5.6 vs. 7.8 years); and to be approved based on phase II studies (65% vs. 29%). Prior to 2004, development times were similar for solid tumor and hematologic malignancy NMEs. Since 2004, development times have decreased by more than 2 years for hematologic malignancy NMEs, but not for solid tumor NMEs. 50% of NMEs approved for hematologic malignancies versus 71% of NMEs for solid tumor diagnoses are included in first-line cancer regimens in current National Comprehensive Cancer Network guidelines. Drugs approved for solid tumor and hematologic indications have similar safety profiles and efficacy; respectively, 30% and 38% carried black box warnings at initial approval, and 15% and 10% had black box warnings added post-approval. Studies confirming efficacy were completed for 89% of NMEs receiving AA for solid tumor indications versus 30% for NMEs receiving AA for hematologic malignancy indications. Concern that sponsors are not completing subpart H commitments has led the FDA to move from basing AA on final results of single-arm phase II trials to interim results of phase III trials. Conclusions: AAs for hematologic malignancy indications are less likely to complete Subpart H commitments. In the current era, development times for NMEs are shorter for hematologic malignancy versus solid tumor indications, principally related to the approval based on Phase II versus Phase III studies. Establishing a global policy that AA approval for cancer drugs should be based on interim results of phase III analyses rather than on final analyses of phase II trials may hamper development of novel therapies for hematologic malignancies. Solide tumor indications Hematologic malignancy indications 1995–2003 (n=21) 2004–2008 (n=10) 1995–2003 (n=11) 2004–2008 (n=9) Drugs receivving AA (%) 29 30 64 33 Orphan drugs (%) 24 40 100 78 Of AAs, Subpart H completion (%) 100 66 27 0 Approval based on phase II trial (%) 33 0 73 78 Median development time (years) 8.4 7.8 8.8 5.2

OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC). A GERCOR study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3504-3504 ◽  
Author(s):  
F. Maindrault-Goebel ◽  
G. Lledo ◽  
B. Chibaudel ◽  
L. Mineur ◽  
T. Andre ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Phase Ii ◽  
Median Duration ◽  
Phase Ii Study ◽  
Phase Iii ◽  
Randomized Phase Ii ◽  
Phase Iii Study ◽  
Large Phase ◽  
Duration Of Disease

3504 Background: The OPTIMOX1 study (JCO 2006) has shown that the strategy of 6 cycles of FOLFOX7 followed by maintenance therapy and FOLFOX reintroduction was as active and better tolerated than FOLFOX4 until progression. The aim of the OPTIMOX2 study was to evaluate a complete stop of chemotherapy after 6 bimonthly cycles of FOLFOX. Methods: Initially planned as a phase III study, OPTIMOX2 was downgraded to a large phase II study since the availability of bevacizumab. Patients (pts) were randomized between an OPTIMOX1 arm: 6 cycles of FOLFOX7 followed by LV5FU until progression and reintroduction of FOLFOX7, and the OPTIMOX2 arm: 6 cycles of FOLFOX7, complete stop of chemotherapy and reintroduction of FOLFOX7 before the tumor progression reached the baseline measures. Results: 187/200 planned pts were included between Feb 2004 and Nov 2005. Response rates were (OPTIMOX1 arm/OPTIMOX2 arm): CR 2%/2%, PR 54%/51%, stable 24%/33%, progression 11%/7%, non assessable 9%/7%. Median PFS were (OPTIMOX1 arm/OPTIMOX2 arm) 36/28 weeks (p=.01), PFS in responders 41/30 weeks (p=.001), PFS in stable patients 34/26 weeks (p=.23). Median duration of disease control (DDC), addition of PFS of first FOLFOX7 administration plus PFS of FOLFOX reintroduction if no progression at first evaluation, was 41 weeks in the OPTIMOX1 arm and 36 in the OPTIMOX2 arm, p=.17. Median duration of chemotherapy-free interval in the OPTIMOX2 arm was 25 weeks (5.7 months). Conclusions: Maintenance LV5FU therapy prolongs PFS. The quality of life of almost 6 months CFI can balance a small advantage in DDC for maintenance therapy. Our next goal is to evaluate maintenance therapy with targeted agents alone. [Table: see text]

Randomised phase II study evaluating weekly docetaxel in combination with cisplatin and 5FU or capecitabine in metastatic oesophago-gastric cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4067-4067 ◽  
Author(s):  
N. Tebbutt ◽  
V. Gebski ◽  
A. Strickland ◽  
D. Gibbs ◽  
E. Walpole ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Haematological Toxicity ◽  
Phase Iii ◽  
Stage Design ◽  
Weekly Docetaxel ◽  
Phase Iii Study ◽  
Recent Phase ◽  
Combination Regimens

4067 Background: Docetaxel (T), cisplatin (C) and 5FU (F) are active agents in oesophago-gastric cancer. A recent phase III study using TCF achieved a survival advantage but was associated with high rates of haematological toxicity (30% incidence of febrile neutropenia/neutropenic infection) as well as non-haematological side effects (Moiseyenko et al, 2005 Pr ASCO abstr 4002). Weekly docetaxel is associated with a lower incidence of haematological toxicity. This randomised phase II study aimed to test weekly docetaxel based combination chemotherapy regimens with the aim of maintaining the activity of docetaxel based combination regimens but reducing toxicity. Methods: Eligibility included; histologically confirmed, metastatic oesophageal or gastric (OG) carcinoma, measurable disease, PS0–2, adequate organ function, no prior treatment, informed consent. Pts were randomised to receive weekly (w) T 30 mg/m2 d1, 8 C 60 mg/m2 d1 F 200 mg/m2/d continuously q 3w or wT 30 mg/m2 d1, d8 and capecitabine (×)1600 mg/m2/d d1–14 q3w. The primary endpoint is confirmed response rate (RR), with each arm analysed independently. Simon’s 2 stage design was used, with 5/21 responses required in the first stage to allow continuation to 48 pts per arm. Results: 79 pts enrolled to date. Protocol specified interim analysis of efficacy after 21 pts per arm and of toxicity after 25 pts per arm ( Table ). In the first 21 pts per arm; 12 responses (11 confirmed) in wTCF arm, 6 responses (5 confirmed) in wTX arm. Trial continues accrual to target of 48 pts per arm. Complete accrual expected by April 2006. Updated data will be presented at the meeting. Conclusions: wTCF and wTX have encouraging activity and and a more favourable toxicity profile than TCF administered 3-weekly. [Table: see text] [Table: see text]

Results of the X-PECT study: A phase III randomized double-blind, placebo-controlled study of perifosine plus capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients (pts) with refractory metastatic colorectal cancer (mCRC).

2012 ◽  
Vol 30 (18_suppl) ◽  
pp. LBA3501-LBA3501 ◽  
Author(s):  
Johanna C. Bendell ◽  
Thomas J. Ervin ◽  
Neil N. Senzer ◽  
Donald A. Richards ◽  
Irfan Firdaus ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Phase Ii ◽  
Median Overall Survival ◽  
Phase Iii ◽  
Controlled Study ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Randomized Phase Ii ◽  
Phase Iii Study

LBA3501 Background: Perifosine (P) is an oral, synthetic alkylphospholipid that inhibits or modifies signal transduction pathways including AKT, NFkB and JNK. A randomized phase II study examined P-CAP vs. CAP in pts with 2nd or 3rd line mCRC. This study showed improvement in mTTP (HR 0.254 [0.117, 0.555]) and mOS (HR 0.370 [0.180,0.763]). Based on these results, a randomized phase III study of P-CAP vs. CAP with a primary endpoint of overall survival (OS) in pts with refractory mCRC was initiated. Methods: The study was a prospective, randomized, double-blind, placebo-controlled randomized phase III trial. Eligible pts had mCRC which was refractory to all standard therapies. Pts randomized 1:1 to Arm A = P-CAP (P 50 mg PO QD + CAP 1000 mg/m2PO BID d1-14) or Arm B = CAP (placebo + CAP 1000 mg/m2 PO BID d 1-14). Cycles were 21 days. Baseline tumor block collection and a biomarker cohort of pts with pre- and on-treatment tumor and blood samples were performed. Results: Between 3/31/10 and 8/12/11, 468 pts were randomized, 234 pts were in each arm. Baseline demographics were balanced between the arms: age < 65y (A: 65%, B: 58.5%), male (A: 57.7%, B: 53.0%), ECOG PS 0 (A: 39.7%, B: 39.7%), K-ras mutant (A: 50.4%, B: 51.3%), and median number of prior therapies (A: 4, B: 4). As of 3/19/12, median follow up was 6.6 months. Median overall survival: Arm A = 6.4 mo, Arm B = 6.8 mo, HR 1.111 [0.905,1.365], p = 0.315. Median overall survival for K-ras WT pts: Arm A = 6.6 mo, Arm B = 6.8 mo, HR 1.020 [0.763,1.365], p = 0.894; K-ras mutant pts: Arm A = 5.4 mo, Arm B = 6.9 mo HR 1.192 [0.890,1.596], p = 0.238. Conclusions: Despite promising randomized phase II data, this phase III study shows no benefit in overall survival adding perifosine to capecitabine in the refractory colorectal cancer setting. Response rate, progression free survival, and safety data will be presented. Biomarker analysis is pending to see if subgroups of patients may have potential benefit.

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