Introduction to Confirmatory Trials

If it has been demonstrated that exposure is related to a relevant clinical outcome, such as efficacy or toxicity, and that exposure can be optimized by PK-guided dosing, it could be logically assumed that PK-guided dosing would result in better treatment outcomes without the need for randomized confirmatory trials.

If it has been demonstrated that exposure is related to a relevant clinical outcome, such as efficacy or toxicity, and that exposure can be optimized by PK-guided dosing, it could be logically assumed that PK-guided dosing would result in better treatment outcomes without the need for randomized confirmatory trials.

Therefore, to accelerate the development process and better characterize the treatment effect of new investigational therapies, other TTE endpoints such as progression-free survival and event-free survival (EFS) are applied as primary efficacy endpoints in some confirmatory trials, either as a surrogate for OS or as a direct measure of clinical benefits.

Therefore, to accelerate the development process and better characterize the treatment effect of new investigational therapies, other TTE endpoints such as progression-free survival and event-free survival (EFS) are applied as primary efficacy endpoints in some confirmatory trials, either as a surrogate for OS or as a direct measure of clinical benefits.

5 Thus, ARD spearheaded the field by providing new, thoroughly peerreviewed findings at an early stage of our understanding of COVID-19 treatment so that others could perform confirmatory trials and patients could benefit timely from this advance.

ADs can be applied from early-phase trials to confirmatory trials.

5 Thus, ARD spearheaded the field by providing new, thoroughly peerreviewed findings at an early stage of our understanding of COVID-19 treatment so that others could perform confirmatory trials and patients could benefit timely from this advance.

ADs can be applied from early-phase trials to confirmatory trials.

Assessment of efficacy in important subgroups – such as those defined by sex, age, race and region – in confirmatory trials is typically performed using separate analysis of the specific subgroup.

Assessment of efficacy in important subgroups – such as those defined by sex, age, race and region – in confirmatory trials is typically performed using separate analysis of the specific subgroup.

As with other approvals under the Accelerated Approval Program, continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.

As with other approvals under the Accelerated Approval Program, continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.

In this study, we describe the methods and designs of breast cancer confirmatory trials published between 2001 and 2020.

In this study, we describe the methods and designs of breast cancer confirmatory trials published between 2001 and 2020.

Findings can inform the development of evidence-based guidance to facilitate design decisions for confirmatory trials.

Findings can inform the development of evidence-based guidance to facilitate design decisions for confirmatory trials.

This model was applied to predict the performance of the entire set of 3024 accessions, and the top predicted performers were sent to Madagascar for confirmatory trials.

This model was applied to predict the performance of the entire set of 3024 accessions, and the top predicted performers were sent to Madagascar for confirmatory trials.

The FDA's Accelerated Approval program is under scrutiny after four drug companies announced plans in recent months to withdraw indications for checkpoint inhibitors that, despite showing early promise, failed to demonstrate a survival benefit in confirmatory trials.

The FDA's Accelerated Approval program is under scrutiny after four drug companies announced plans in recent months to withdraw indications for checkpoint inhibitors that, despite showing early promise, failed to demonstrate a survival benefit in confirmatory trials.

Blinded, placebo-controlled confirmatory trials of higher methodological quality are warranted, especially using oral, short-term BCAAs-enriched supplements within the context of recent ERAS programs.

Blinded, placebo-controlled confirmatory trials of higher methodological quality are warranted, especially using oral, short-term BCAAs-enriched supplements within the context of recent ERAS programs.

Further investigation of PB-201 100 mg twice daily in confirmatory trials is warranted.

Further investigation of PB-201 100 mg twice daily in confirmatory trials is warranted.

Although these findings require replication in both retrospective and prospective confirmatory trials, they emphasize the need to incorporate similar genetic analyses of choline-related polymorphisms in other FASD-choline trials, and to test for similar associations within the general FASD population.

Although these findings require replication in both retrospective and prospective confirmatory trials, they emphasize the need to incorporate similar genetic analyses of choline-related polymorphisms in other FASD-choline trials, and to test for similar associations within the general FASD population.

As part of this approval, the manufacturer must conduct post-approval studies—known as phase IV confirmatory trials—to “verify the anticipated clinical benefit.

These results warrant further validation in larger confirmatory trials.

As part of this approval, the manufacturer must conduct post-approval studies—known as phase IV confirmatory trials—to “verify the anticipated clinical benefit.

These results warrant further validation in larger confirmatory trials.

Over the past 6 years, the FDA has approved six ICIs for more than 75 oncological indications (35 through an accelerated pathway), and the term “dangling accelerated approvals” was coined: duplicates or similar indications for which the required confirmatory trials failed to show a clear benefit, and yet their marketing authorization continued [3].

However, one of the barriers to the uptake of Bayesian adaptive designs for confirmatory trials is limited experience with how they may perform compared to a frequentist design.

Over the past 6 years, the FDA has approved six ICIs for more than 75 oncological indications (35 through an accelerated pathway), and the term “dangling accelerated approvals” was coined: duplicates or similar indications for which the required confirmatory trials failed to show a clear benefit, and yet their marketing authorization continued [3].

However, one of the barriers to the uptake of Bayesian adaptive designs for confirmatory trials is limited experience with how they may perform compared to a frequentist design.

Positive findings from modern trials are catalysing developments, but it is questionable whether current confirmatory trials are sufficient for advancing our understanding of safety and best practice.

Positive findings from modern trials are catalysing developments, but it is questionable whether current confirmatory trials are sufficient for advancing our understanding of safety and best practice.

In confirmatory trials, the rates of missed residual cancer [false-negative rates (FNRs)] were unacceptably high (> 10%).

In confirmatory trials, the rates of missed residual cancer [false-negative rates (FNRs)] were unacceptably high (> 10%).

BackgroundFeasibility and pilot studies are recommended prior to embarking on large-scale costly confirmatory trials.

While some small studies observed beneficial effects of HRV biofeedback on dysautonomia in patients with depressive disorders, larger confirmatory trials are lacking.

High dose FSS should be tested in confirmatory trials.

Increased protein delivery may improve extubation rate which has positive patient-centred and financial implications, warranting larger confirmatory trials.

Introduction Evidence indicates e-cigarettes can help people quit smoking; however, more confirmatory trials are needed.

Further confirmatory trials are required.

Licenses for conditional approval of regenerative products are valid for 5 years and sponsors needs to submit the results of the confirmatory trials.

A target dose of 250 Gy will provide a further margin of safety, until large‐scale confirmatory trials are completed.

Objective To compare the end points used in preapproval trials leading to accelerated approval with the end points used in the required confirmatory trials that verified clinical benefit and to update the outcomes of accelerated approvals with confirmatory trials that were ongoing at the time of FDA's review.

Larger confirmatory trials with longer follow-up periods are required before any change in clinical practice can be recommended.

The reason is that any analysis method for handling missing data comes with unverifiable assumptions, and in confirmatory trials we want to limit those kinds of assumptions.

Many confirmatory trials are now continuing to collect data from subjects in a study even after they have prematurely discontinued study treatment as this event is irrelevant for the purposes of a treatment policy estimand.

The second and third examples are confirmatory trials in severe asthma and rheumatoid arthritis respectively.

Potential pathways forward include closer collaboration between regulators, pharmaceutical companies and payers to enhance the generation of rapid and comparative confirmatory trials in a safe and fair manner, with minimal patient exposure as required to achieve robust evidence.

Although 5 indications (accounting for 40% of identified confirmatory trials) ultimately secured FDA or European Medicines Agency approval, clinical trials for 22 (67%) indications generated clinical agnosticism, a term the authors coined to describe exploratory, underpowered trials that suggested a new clinical benefit.

After exploratory drug development, companies face the decision whether to initiate confirmatory trials based on limited efficacy information.

Given that the comparative analysis was derived from few randomized publications, large confirmatory trials should be carried out before a strong recommendation is made in favor of TNT.

This chapter gives an overview of statistical design and analysis methods that may be applied to the screening tests and confirmatory trials such as those presented in this book.

If favorable early findings from exploratory trials are not promptly followed by confirmatory trials, then physicians, patients, and payers can be left uncertain about a drug’s clinical value (clinical agnosticism).

However, in light of the small number of patients recruited by the single study investigating costoclavicular blocks, further confirmatory trials are required.

023) and confirmatory trials (-0.

RITE may be a second-line therapy for non-CIS recurrence following BCG failure; however, confirmatory trials are needed.

Confirmatory trials with optimized patient selection criteria and more active drugs may be required to demonstrate a survival benefit from intrathecal pharmacotherapy.

Based on data from confirmatory trials, safety profiles of three BRAFi+MEKi combinations were reviewed, that is, dabrafenib plus trametinib, vemurafenib plus cobimetinib and encorafenib plus binimetinib.

Further, machining parameters are optimized using genetic algorithm and confirmatory trials are performed using optimized conditions.

Research is currently investigating new ways to de-emphasize side-effects whilst still upholding informed consent, but larger confirmatory trials with suitable control groups are needed.

More recently, Federico and colleagues found that small exploratory trials might encourage offlabel prescribing by generating ‘clinical agnosticism’ not addressed in confirmatory trials within 5 years.

Phase 4 trials are considered as confirmatory trials after completion of a successful phase 3 randomized controlled trial (RCT).

The ICH E9(R1) draft addendum builds on that research to outline key principles in choosing estimands for clinical trials, primarily with focus on confirmatory trials.

It was found that 89% of clinical development programs included several doses in the first‐in‐patient trial, 43% proceeded directly to confirmatory trials after the first‐in‐patient trial, and 52% included multiple doses in confirmatory development.

8,9 The initial promise of interventions such as protocolised, goaldirected haemodynamic resuscitation for early septic shock (early goaldirected therapy),3,10 tight glycaemic control11,12 and recombinant human activated protein C for severe sepsis13 has not been reproduced in subsequent confirmatory trials.