OP173 Eligibility Criteria For “Accelerated Access” Approval: A Global Survey

2018 ◽  
Vol 34 (S1) ◽  
pp. 63-64
Author(s):  
Olina Efthymiadou ◽  
Mackenzie Mills ◽  
Victoria Tzouma ◽  
Panos Kanavos
Keyword(s):  
Phase Iii ◽  
Eligibility Criteria ◽  
Level Of Evidence ◽  
Early Access ◽  
Life Saving ◽  
Phase Iii Trials ◽  
Scientific Opinion ◽  
Named Patient Programme ◽  
Larger Sample ◽  
Evidence Generation

Introduction:Several early access schemes (EAS) exist, which aim to accelerate patient access to new, potentially life-saving therapies. While some information exists on key schemes and their modalities, the determinants that drive adoption of a new medicine under an EAS remain unclear. We aimed to map eligibility criteria for inclusion of new medicines into the different EAS available across countries.Methods:Health technology assessment (HTA) stakeholders across 23 countries globally were invited via email to complete a web-survey with questions on (i) items that define product eligibility for EAS designation, (ii) standards for minimum level of evidence, monitoring, and additional evidence generation for early access products, and (iii) funding arrangements for these products across settings and types of schemes. Anonymized responses were analysed using descriptive statistics.Results:Fourteen responses from 10 countries (including Belgium, England, France, Japan and Mexico, among others) demonstrated that “unmet clinical need” was paramount for EAS designation across all countries and types of schemes. The next most important factors were “phase-III trials underway” and “serious condition” for Compassionate Use Programme (CUP) and Named Patient Programme (NPP) inclusion (21 percent and 20 percent of respondents, respectively). “Measures in place to monitor risk” was key for CUP and NPP designation (43 percent and 27 percent of respondents, respectively), followed by “innovative product designation” for CUP and “scientific opinion” for NPP eligibility (14 percent and 23 percent of respondents, respectively). “No specific monitoring requirements” exist in Germany and Austria, whereas “reporting of adverse events” is crucial in France, England, Japan and Spain. NPP eligible products are mainly funded at a negotiated price and CUP designated products are largely provided by manufacturers free-of-charge (i.e. England, Scotland, Germany).Conclusions:Eligibility criteria/requirements and funding arrangements for early access vary considerably across settings and their respective EAS. Information from a larger sample of countries is required for an all-encompassing mapping of the early access products’ characteristics.

OP132 What Future For Drugs After An Early Dialogue Procedure?

2019 ◽  
Vol 35 (S1) ◽  
pp. 30-30
Author(s):  
Judith Fernandez ◽  
Camille Thomassin ◽  
Mathilde Grande ◽  
Chantal Bélorgey ◽  
Christian Thuillez ◽  
...  
Keyword(s):  
Clinical Development ◽  
Added Value ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Pharmaceutical Manufacturers ◽  
Medical Need ◽  
Pivotal Study ◽  
Phase Iii Trials ◽  
Evidence Generation

IntroductionThe French health technology assessment (HTA) body, Haute Autorité de la Santé (HAS), started to provide early advice on evidence generation plans to pharmaceutical manufacturers in 2010. It became an official mission in 2016. Requests are eligible when the product has a new mechanism of action, if there is an unmet or partially met medical need in the claimed indication and when the pivotal study has not yet started. This analysis aims to provide a first overview of clinical developments for which pharmaceutical companies sought an early dialogue with HAS.MethodsFor each product that went through an early dialogue procedure with HAS, information regarding the clinical development was collected on pharmaceuticals companies’ pipelines, clinicaltrials.gov, the website of the European Medicine Agency (EMA) and HAS's internal database.ResultsBy the end of 2018, HAS has performed 84 early dialogues of which 53 were conducted in collaboration with the EMA and/or others European HTA bodies. They were mainly focused on phase III trials. Following early dialogue, the clinical study for which the company sought advice was not yet implemented in 25 cases. When the clinical trial was effectively launched, results were negative in 10 cases, positive in 11 cases and the study was still ongoing for 29 products. In nine cases, the clinical development was officially withdrawn or suspended before the initiation of the trial. Overall, only eight medicinal products were appraised by HAS, they all obtained a clinical added value score.ConclusionsThe success rate of clinical development for products that underwent an early dialogue procedure tends to be higher than data from literature, although it is likely to decrease in follow-up analysis. This could be partially explained by HAS's eligibility criteria that restrict early dialogues to promising products and by the scientific recommendations provided to pharmaceuticals companies.

scholarly journals Effectiveness studies: advantages and disadvantages

2011 ◽  
Vol 13 (2) ◽  
pp. 199-207 ◽  
Keyword(s):  
Relevant Information ◽  
Phase Iii ◽  
Design Issues ◽  
Level Of Evidence ◽  
Advantages And Disadvantages ◽  
Treatment Conditions ◽  
Phase Iii Trials ◽  
Methodological Problems ◽  
Effectiveness Studies ◽  
Phase Iv

In recent years, so-called "effectiveness studies," also called "real-world studies" or "pragmatic trials," have gained increasing importance in the context of evidence-based medicine. These studies follow less restrictive methodological standards than phase III studies in terms of patient selection, comedication, and other design issues, and their results should therefore be better generalizable than those of phase III trials. Effectiveness studies, like other types of phase IV studies, can therefore contribute to knowledge about medications and supply relevant information in addition to that gained from phase III trials. However, the less restrictive design and inherent methodological problems of phase IV studies have to be carefully considered. For example, the greater variance caused by the different kinds of confounders as well as problematic design issues, such as insensitive primary outcome criteria, unblinded treatment conditions, inclusion of chronic refractory patients, etc, can lead to wrong conclusions. Due to these methodological problems, effectiveness studies are on a principally lower level of evidence, adding only a complementary view to the results of phase III trials without falsifying their results.

Treatment-associated mortality in head and neck cancer: Analysis of phase III trials.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6064-6064
Author(s):  
Marina Shcherba ◽  
Shankar Viswanathan ◽  
Dukagjin Blakaj ◽  
Madhur Garg ◽  
Missak Haigentz
Keyword(s):  
Relative Risk ◽  
Head And Neck ◽  
Early Death ◽  
Early Mortality ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Curative Intent ◽  
Mortality Statistics ◽  
Risk Of Death ◽  
Phase Iii Trials

6064 Background: Chemoradiotherapy is an accepted standard for patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). Although acute and long-term toxicities of this approach are known, little is known about early mortality associated with curative-intent treatment. Methods: We reviewed 45 phase III trials of curative-intent radiotherapy in SCCHN published from 2000-2012 for adequate reporting of early mortality defined as deaths during and within 3 months of therapy, regardless of attribution. We estimated pooled proportions of deaths during prescribed therapy using a random effects model of radiotherapy alone (RT), concurrent chemoradiotherapy (CCRT) and induction chemotherapy (IC) regimens. The relative risk of death during CCRT vs. RT and CCRT/IC vs. RT were estimated. Results: Although all trials reported early mortality statistics, definitions had wide variability, and only 34 trials (75%) met adequate reporting characteristics. Ten trials excluded enrolled patients who died prior to initiating therapy. Of studies reporting early mortality statistics, crude frequency of death during prescribed therapy was 2.7% (308/11362). The pooled estimated rates of death observed during RT alone was 1.7% (SE: 0.3, I2=89.2%) from 29 studies, while 2.8% (SE: 0.4, I2=64.9%, 19 studies) and 3.1% (SE: 0.5, I2=53.5%, 9 studies) for CCRT and IC regimens, respectively. The pooled relative risk for death in CCRT compared to RT treatment was 1.08 (95%CI: 0.78, 1.48, p=0.63, I2=0, 15 studies). The relative risk for death in CCRT or IC therapy compared to RT was 1.06 (95%CI: 0.77, 1.45, p=0.72, I2=0, 15 studies). When reported, most early deaths were attributed to infectious complications or cardiovascular events. Conclusions: Early death remains an uncommon but important complication of curative-intent radiotherapy in SCCHN that necessitates consistent reporting. Despite strict eligibility criteria and protocol-defined care, treatment-associated death occurs with all regimens, though no clear increase was observed with CCRT/IC regimens over RT alone. Early mortality should be considered during treatment planning, particularly for patients with considerable comorbidities.

scholarly journals Real-world validity of randomized controlled phase III trials in newly diagnosed glioblastoma: to whom do the results of the trials apply?

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Erlend Skaga ◽  
Marthe Andrea Skretteberg ◽  
Tom Børge Johannesen ◽  
Petter Brandal ◽  
Einar O Vik-Mo ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Real World ◽  
Performance Status ◽  
Geographical Area ◽  
Eastern Cooperative Oncology Group ◽  
University Hospital ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Eligibility Criteria ◽  
Phase Iii Trials

Abstract Background The survival rates in population-based series of glioblastoma (GBM) differ substantially from those reported in clinical trials. This discrepancy may be attributed to that patients recruited to trials tend to be younger with better performance status. However, the proportion and characteristics of the patients in a population considered either eligible or ineligible for trials is unknown. The generalizability of trial results is therefore also uncertain. Methods Using the Cancer Registry of Norway and the Brain Tumor Database at Oslo University Hospital, we tracked all patients within a well-defined geographical area with newly diagnosed GBM during the years 2012–2017. Based on data from these registries and the medical records, the patients were evaluated for trial eligibility according to criteria employed in recent phase III trials for GBM. Results We identified 512 patients. The median survival was 11.7 months. When we selected a potential trial population at the start of concurrent chemoradiotherapy (radiotherapy [RT]/ temozolomide [TMZ]) by the parameters age (18–70 y), passed surgery for a supratentorial GBM, Eastern Cooperative Oncology Group (ECOG) ≤2, normal hematologic, hepatic and renal function, and lack of severe comorbidity, 57% of the patients were excluded. Further filtering the patients who progressed during RT/TMZ and never completed RT/TMZ resulted in exclusion of 59% and 63% of the patients, respectively. The survival of patients potentially eligible for trials was significantly higher than of the patients not fulfilling trial eligibility criteria (P < .0001). Conclusions Patients considered eligible for phase III clinical trials represent a highly selected minority of patients in a real-world GBM population.

scholarly journals Eligibility criteria and endpoints in metastatic renal cell carcinoma trials.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 465-465
Author(s):  
Sarah Wong ◽  
David I. Quinn ◽  
Georg A. Bjarnason ◽  
Scott A. North ◽  
Srikala S. Sridhar
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Phase Iii Trials ◽  
The One ◽  
Meta Analyses

465 Background: Treatments for metastatic renal cell carcinoma (mRCC) are often compared across trials, but trial eligibility criteria and endpoints differ. In Sept 2015, DATECAN published recommendations for time-to-event endpoints in mRCC trials. The success of their efforts to harmonize endpoints has not yet been assessed. Methods: We assessed eligibility criteria and endpoints from 18 Phase III mRCC trials starting from 2003 onwards. We also assessed 4 Phase III trials submitted after Sept. 2015 for compliance with DATECAN recommendations. Results: Among the 18 trials, consistent criteria were: absolute neutrophil count ≥1,500/µL, platelet count ≥100,000/µL, and bilirubin ≤1.5xULN. However, the following differed in requirements and measures used: see table.The 4 newer trials did not entirely follow DATECAN’s recommendations. Although their primary endpoint is progression free survival (PFS) as recommended, 3/4 trials do not define PFS, and the one that does includes death from any cause instead of DATECAN’s “death from kidney cancer.” Conclusions: Key eligibility criteria were somewhat inconsistent across phase III mRCC trials, and newer trials’ endpoints did not align with DATECAN’s recommendations. Not only is greater standardization needed to facilitate meta-analyses and cross-trial comparisons, but as evident from lack of adherence to DATECAN’s recommendations, greater promotion and enforcement of recommendations is needed to harmonize trial design and improve comparability.[Table: see text]

scholarly journals Level of Evidence for FDA Drug Approvals in Pivotal Clinical Trials of Hematological Malignancies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-6
Author(s):  
Samer Al Hadidi ◽  
Carlos A. Ramos
Keyword(s):  
Clinical Trials ◽  
Early Phase ◽  
Hematological Malignancies ◽  
Phase Iii ◽  
Clinical Activity ◽  
Level Of Evidence ◽  
Phase Iii Clinical Trials ◽  
Early Phase Trials ◽  
Phase Iii Trials ◽  
Drug Approvals

BACKGROUND Clinical trials are integral to improve treatment outcomes for patients with hematological malignancies. Although early phase (I/II) clinical trials may provide evidence of clinical efficacy, the main goal for early phase trials is to assess safety signal. Results of phase III clinical trials provide the strongest evidence to support the use of new cancer medications. The Food and Drug Administration (FDA) is responsible to ensure appropriate control and supervision of pharmaceutical drugs. METHODS On the basis of publicly available study protocols and FDA reviews, the authors reviewed the level of evidence in 52 clinical trials supporting 49 drug approvals from 2016 to 2020. Data cut point was May 2020. These trials resulted in approval of medications to treat leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, myeloproliferative neoplasms and multiple myeloma. RESULTS A total of 52 clinical trials were assessed in the 5 years period. Phase III trials supported 61.5% while earlier phase trials supported 36.5% of subsequent FDA hematological malignancies approvals. The level of evidence to support FDA approvals improved with time with 50% of approvals in 2016 and 2017 supported by phase III clinical trials compared to 69% in 2019. Approvals were based on early phase trials in mantle cell lymphoma (100%), chronic myeloid leukemia (100%), diffuse large B cell lymphoma (100%), classic Hodgkin's lymphoma (67%) and acute myeloid leukemia (56%). Phase III trials enrolled 87% of the patients (14238 from16429 patients). Eighteen drug approvals (37% of all approvals) were based on 13% of the total number of patients in the studied period. CONCLUSIONS Level of evidence to support drug approvals in hematological malignancies was based on early phase trials in more than a third of the times. Although early phase studies are appropriate for safety signals, further clinical activity assessment should be done to support the use of new drugs to treat hematological malignancies. Previous successful early phase studies failed to show clinical activity in phase III studies. Despite the fact that use of new approved drugs based on early phase studies evidence may be needed, patients and healthcare providers should be aware of such possibility when using newly approved medications. Figure Disclosures Ramos: Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Kuur Therapeutics: Research Funding.

EXTRA Trial-Evaluation of capecitabine treatment with radiotherapy (RT) in anal cancer: Preliminary results on toxicity and outcome

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14085-14085
Author(s):  
R. Glynne-Jones ◽  
H. Meadows ◽  
S. Wan
Keyword(s):  
Chest Pain ◽  
Anal Carcinoma ◽  
Complete Response ◽  
Early Response ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
End Of Treatment ◽  
Phase Iii Trials ◽  
Pre Treatment ◽  
Grade 3

14085 Background: Phase III trials have shown RT + 5-Fluorouracil (5-FU) + mitomycinC (MMC) as the standard treatment for patients with epidermoid anal carcinoma. The objective of this trial is to determine if capecitabine in combination with MMC has a similar outcome in terms of complete response (CR) rate and toxicity to a 5-day infusion of 5-FU. Capecitabine is a rational alternative to 5-FU as these cancers express high levels of thymidine phosphoralase. Methods: Main eligibility criteria are histologically proven anal carcinoma (epidermoid, squamous, basaloid), fit to receive capecitabine and MMC and ineligible for the ongoing phase III UK trial, ACT II. Exclusion criteria include complete local excision, prior chemoradiation, uncontrolled cardiovascular disease and known HIV+ve. All patients receive: 50.4Gy in 28F(RT) and capecitabine 1650mg/m2/day on each RT treatment day (M-F) over 6 weeks. In addition patients receive MMC 12mg/m2, day 1 only. Assessment of response is by CT scan at 4 wks post chemoradiation. Results: To date 18/30 patients have been registered. Pre-treatment characteristics are: median age 59 yrs (44–85); 7 male, 11 female; 13 Canal, 5 Margin; 5T1, 4T2, 6T3, 2T4, 1Tx; 4N+ve, 13N-ve, 1Nx. Data on 14 evaluable pts are presented here. RT compliance: 12 pts completed planned treatment, treatment was interrupted in 2 cases (chest pain 1; machine breakdown 1). Chemotherapy compliance: 10 pts completed protocol treatment, in 3 pts chemotherapy was affected due to toxicity (1 dose reduced, 2 stopped early 1 due to chest pain and 1 due to grade 3 skin and diarrhoea). One patient decided to stop treatment. Grade 3 toxicity was reported in 2 pts during treatment: dyspnoea 1, diarrhoea 1. Four weeks post chemoradition, 10 had CR, 3 had partial response and 1 pt was not assessable. Thirteen pts are alive and disease free at a median follow-up of 6 months (range 1 -13). One pt has relapsed in an inguinal node 9 months after the end of treatment following a previous CR. Conclusions: This early information suggests that this regimen can be given without interruption and with acceptable toxicity. The early response data is encouraging and the trial aims to reach target accrual by Summer 2006. Educational grant provided by Roche pharmaceuticals. [Table: see text]

Efficacy of low-dose capecitabine in metastatic breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1065-1065
Author(s):  
Caitlin Bertelsen ◽  
Lingyun Ji ◽  
Christy Ann Russell ◽  
Darcy V. Spicer ◽  
Agustin Garcia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Single Agent ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Flat Dose ◽  
Measurable Disease ◽  
Phase Iii Trials

1065 Background: The FDA-approved dose of capecitabine (cape) of 1250mg/m2 twice daily (BID) is associated with treatment-limiting toxicities. Published reports suggest that lower starting doses of cape can be as effective as the approved dose in treating metastatic breast cancer (MBC). We compared the efficacy of lower than previously published doses of cape with results of registrational Phase III trials using the approved dose. Methods: We performed a retrospective analysis of patients treated at the University of Southern California hospitals who received cape as the first, second, or third line of chemotherapy for MBC to determine the progression-free survival (PFS) associated with low starting doses. The primary endpoint was PFS among patients with measurable disease, and secondary aims were to analyze the relationships between PFS and various clinical characteristics for all patients. Results: Patients (n=84) received a median cape dose of 565 mg/m2 BID, often administered as a flat dose (not adjusted for body surface area) of 1000 mg BID. Median PFS among patients with measurable disease (n=62) was 4.1 months (95% confidence interval or CI = 2.9-5.7), which was similar to the median PFS values of 4.4 months (95% CI = 4.14-5.42, n=480) (Sparano et al. JCO 2010;28:3256) and 4.2 months (95% CI = 3.81-4.50, n=377) (Thomas et al. JCO 2008;25:5210) for single-agent cape reported in the major trials with similar eligibility criteria. Among all patients, PFS was shorter in measurable disease, triple negative and HER2+ subtypes, and was similar in all lines of therapy. Only two patients (2.4%) discontinued cape due to toxicity. Conclusions: These data support the efficacy of very low doses of cape for MBC. Prospective randomized controlled trials testing lower starting doses of cape are needed to optimize the benefit/risk ratio. [Table: see text]

scholarly journals CLRM-11. BENCH TO BEDSIDE NEURO-ONCOLOGY: ADVOCATING FOR A CLINICALLY RELEVANT STRATEGY AS UNDERSCORED BY THE PANDEMIC

2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv3-iv3
Author(s):  
Timothy Brown ◽  
Alireza Mansouri ◽  
Samer Zammar ◽  
Michael Glantz
Keyword(s):  
Basic Science ◽  
Science Research ◽  
Phase Iii ◽  
Preclinical Studies ◽  
Class Iii ◽  
Level Of Evidence ◽  
Laboratory Findings ◽  
Therapeutic Trials ◽  
Basic Science Research ◽  
Phase Iii Trials

Abstract INTRODUCTION The basic science research endeavor has been abundantly and astonishingly successful in the last three decades in elucidating the mechanisms of neuro-oncologic disease and in suggesting therapeutic strategies. Clinical successes have lagged behind, and translation of promising laboratory findings into clinical practice is rare. We hypothesize that one important reason for this discordance is the use of different paradigms for designing laboratory and clinical trials, and that utilizing clinically relevant procedures could improve laboratory study impact. METHODS We identified all pre-clinical neuro-oncology therapeutic trials published in four high-impact journals between 11/2018 and 4/2019 and assigned a level of evidence (LOE) to each study using the American Academy of Neurology evidence classification system. We then identified all phase III trials of therapeutics for COVID and performed the same analysis on all preclinical studies preceding the trials. RESULTS Of the 26 neuro-oncology articles identified, 85% had a LOE of IV and 15% were class III. An analysis of successful human trials showed significantly more high quality laboratory studies supporting “successful” compared to “unsuccessful” trials (p=0.048). This same pattern was identified in phase III trials of COVID. Twenty antiviral studies failed to meet the primary endpoint; all were preceded by class III or IV LOE preclinical studies. Eight evaluable phase three studies of COVID vaccines were identified, all of which met their primary endpoints. These were supported with a mix of Class I/II (n=4) and III/IV (n=4) preclinical studies. Higher LOE by AAN criteria is associated with successful COVID therapeutic trials (p=0.0034). CONCLUSIONS Despite rigorous, elegant, and enlightening laboratory experiments, successful translation to human therapeutics remains rare. Envisioning basic science research through the lens of clinical therapeutics represents a challenging but surmountable paradigm shift that may reverse this pattern and create a more successful research enterprise in neuro-oncology and beyond.

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