Oncology Clinical Trials Successful Design Conduct And Analysis Pdf
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- Oncology Clinical Trials: Successful Design, Conduct and Analysis
- Clinical Trials
- Oncology clinical trials : successful design, conduct, and analysis
Clinical trials are experiments or observations done in clinical research.
Oncology Clinical Trials: Successful Design, Conduct and Analysis
Regret for the inconvenience: we are taking measures to prevent fraudulent form submissions by extractors and page crawlers. Received: August 20, Published: September 1, Data and analysis considerations in oncology clinical trials. Biom Biostat Int J. DOI: Download PDF. Background: Oncology clinical trials are distinct from trials in other disease areas in its unique patient population, treatment and toxicity monitoring, endpoint assessment and follow-up.
Promising innovative therapies to treat and prevent cancer have made oncology a fertile ground to conduct clinical research. Purpose: To raise awareness and discuss relevant data and analysis issues that are critical to the ultimate success of oncology clinical trials. Methods: We review data collection, cleaning, and analysis considerations in oncology clinical trials in the area of dosing, adverse events, tumor assessments, and survival follow-up.
Operational issues relating to statistical analysis milestones and validation are also discussed. Results: Upfront planning and careful considerations in data collection, monitoring, cleaning, and analyses have major impacts on the quality and conduct of the trial. Clear and appropriate data presentations not only enhance the interpretability of the results but also boost the confidence in the analyses.
Conclusion: Collaboration and coordination among multiple stakeholders and different functions of the trial sponsor are essential at all stages of a clinical trial. Special emphasis should be given to systematic approaches to collect appropriate data and to monitor data issues as early as possible to ensure quality in execution and clarity in reporting of oncology clinical trials.
Keywords: oncology, clinical trial, treatment emergent adverse event, dose intensity, RECIST criteria, data cut-off date, event-driven analysis, analysis validation. Clinical trials have become a more complex undertaking. Trials that enroll patients globally are commonplace. Biomarker trials involving companion diagnostics become more sophisticated and require coordination and seamless execution from multiple stakeholders.
Innovative trial designs involve upfront planning and attention to details in execution. These factors along with regulatory requirements have placed a greater burden on the sponsors to ensure that the data collected from the trials have unimpeachable integrity, quality, and validity to draw conclusions with respect to the objectives of the trials. Data are arguably the ultimate measure of clinical trial performance.
Appropriate trial design, well-thought-out case report forms CRF and clear CRF completion instructions are among the first steps to ensure data are consistenly collected in order to achieve the trial objectives. These efforts are augmented by ongoing data cleaning and monitoring to ensure data accuracy.
Monitoring visits are one of the most resource-intensive activities to ensure valid data are collected against source documents. The US Food and Drug Administration FDA has provided guidance 1 on an integrated approach to monitor clinical trial quality and subject safety through a risk-based centralized monitoring approach.
The main idea is to implement a central, systematic, and ongoing review of data which allows the monitoring to be more focused and data-driven. Continued advances in technology, data sharing standards including Clinical Data Interchange Standards Consortium CDISC , 2 and the increasing sophistication of data visualization tools promise to increase efficiency and reduce clinical trial cost.
In this article, we focus on data collection and analysis issues in oncology clinical trials. In particular, we will take a deeper dive on data related to dosing, adverse events AEs , tumor assessments, and overall survival. Special emphases are given to considerations in collecting relevant data and in identifying data issues in oncology clinical trials.
We strongly believe that the biggest bang for the buck in monitoring trial conduct and ensuring quality comes from early identification of issues and trends so preventative and remedial actions can be put in place to avoid costly damages to the trial. Analysis and reporting considerations are also discussed to highlight the need for effective and clear presentation of data. In oncology trials, treatment exposure is not only informative in its own right but also acts as an indirect measure of tolerability and even efficacy.
Actual versus prescribed dose : Dosing information is commonly captured in a log format with key elements such as start date, stop date, actual dose, and dose change reasons. When dosing records do not cover a period of time continuously, it is common to assume that there are no doses given during the gap. However, one cannot be certain if this is due to data entry error that there is actually no dosing gap.
Some sponsors collect prescribed dose in the dosing log along with the actual dose. We think it provides useful information and suggest that care be given to the CRF design. A CRF with both the prescribed and actual dose along with the respective reasons of dose change can accurately capture the scenario.
Table 1 outlines a sample dosing CRF incorporating the actual dose and prescribed dose. If the protocol specified treatment duration is 20 days, then the patient stopped after only 10 days of treatment. An alternative unconditional dose intensity and relative dose intensity may be derived as the following:. Dose intensity and compliance : Dose intensity DI is expressed as the amount of dose per unit of time.
It is calculated by dividing the actual cumulative dose by treatment duration. It is common in trials where treatment is given until disease progression. Dose intensity calculation is straightforward based on the above definition. However, in settings where treatment is given for a fixed period of time, for example in the adjuvant breast cancer setting where the standard of care is one year of trastuzumab treatment after surgery, for patients with HER2-positive disease, alternative definition of dose intensity may be relevant.
If the protocol specified treatment period is for one year and a subject has stopped treatment after 6 months on drug, dose intensity may be calculated for this patient as the cumulative dose over 6 months or over one year. The former definition may be viewed as dose intensity conditional on the patient being treated.
The latter definition insists on the protocol specified treatment duration regardless of the actual treatment duration unconditional. While we are not advocating one definition of dose intensity over the other as the emphasis may be different depending on the situation, we recommend greater clarity and transparency when reporting results.
In calculating treatment duration, it is common practice to add the dosing interval after the last dose. If prescribed dose is collected, prescribed dose intensity P-DI can also be obtained similarly. Relative dose intensity RDI is calculated as the actual dose intensity divided by the protocol specified dose intensity.
It compares the actual dose and schedule captured in dose intensity with the protocol specified intensity protocol specified dose and schedule. With the exception of over-dose which should be monitored and flagged , a higher RDI represents closer adherence to the protocol specified dose and schedule. Prescribed relative dose intensity P-RDI can also be obtained analogously reflecting prescribed rather than the actual dose and schedule relative to the protocol dosing specification.
One may also be interested in calculating adherence ratio AR , defined as the ratio between the actual dose intensity divided by the prescribed dose intensity. AR compares the actual dose relative to the prescribed dose with the understanding that prescribed dose has taken into account dose changes, if any, prescribed by the treating physician.
Table 1 also includes hypothetical data of a patient to illustrate dose intensity and adherence calculations. By providing the details, we wish to highlight the nuances in summarizing dose exposure and intensity. Dose intensity is a single summary measure incorporating both dose and treatment duration. When a treatment is given in cycles, as is common in oncology, summary measuressuch as dose received per cycle and percent of planned dose received per cycle may be more appealing.
However, dose intensity and relative dose intensity may still be relevant as they capture delays of cycle time due to the need to manage treatment toxicities. The collection of adverse events include description of the event, start date, stop date, seriousness, severity, relationship to study drug, actions taken and outcome.
Typically, AEs are collected during the screening phase after informed consent has been signed and continues until the end of the protocol specified safety follow-up time. Ensuring the quality of safety data capture is the foundation of all pharmacovigilence activities. Common checks of the AE data include review of overlapping dates when more than one episodes of the same event of different severity are reported. Actions taken due to an AE should also be cross-checked against dosing data if it leads to a dose reduction or against the end of treatment reason if it leads to the discontinuation of treatment.
A more complete suite of cross checks with other data in the database such as labs, concomitant medication, death, or hospitalization should be a part of the standard built-in data cleaning process. Treatment-emergent adverse events : Because AEs are collected after the date the informed consent is signed which may be prior to the initiation of treatment, treatment emergent adverse events TEAEs are often the primary focus of the safety analyses.
The idea of TEAE is to include any AE that occurs or worsens after the initiation of treatment and before a pre-defined period of time e. ICH E9 3 defines TEAE as an event that emerges during treatment but having been absent during pre-treatment, or worsens relative to the pre-treatment state.
There are some controversies when implementing this. It seems that cases 1 and 3 may not be considered as TEAEs since case 1 may be considered as a continuation of the same event and case 3 may be a continuation of the same event but with a lower grade. However, for cases 2 and 4, the AEs are recorded by investigators as separate episodes starting on Day 5. Because the severity grades are no worse than the pre-existing episode, one may argue the events are pre-existing and should not be counted as TEAEs.
Following this logic, what about events of the same severity which start on Day 15 rather than on Day 5? One may be hard pressed to not include separate events long after a subject has received the first dose and has continued to receive doses. We advocate a simple and inclusive approach in that any AEs with a start date on or after the first dose date and within the pre-defined period after the last dose should be considered as TEAE regardless of pre-treatment conditions.
The TEAE summary should be complemented by a separate summary of any AEs not considered as treatment emergent AEs occurred pre-treatment or post the pre-defined period after the last dose. When applicable, and depending on the disease area, more in-depth summaries of TEAE taking into account of pre-treatment conditions may be explored. Finally, we want to emphasize the importance of providing clear and specific CRF completion instructions to the sites on adverse events that should be recorded as separate events and events that should be considered as continuing without an end date.
In our experiences, this is an area that sponsors should proactively engage the sites during the study setup phase. Post treatment AE recorded as a separate entry from the pre-treatment record. Grade 2 headache started 5 days before the first dose, ended on Day 3 Day 1 is the first dose.
Tumor may be assessed over time by multiple modalities in oncology trials. These assessments contribute to the definition of key endpoints such as response rate and progression free survival PFS. Any modifications by the sponsor of the criteria should be documented in the protocol and in a radiology review charter. Automated response assessment : There are three components in the overall tumor response assessment when RECIST criteria are used: target lesion response, non-target lesion response, and the appearance of a new lesion.
Each individual lesion identified at the baseline target or non-target lesion are tracked and entered into the CRF. Investigator assessments of response of the target, non-target, and new lesions along with an overall response assessment are provided at each protocol specified tumor assessment time.
Typically, investigators are expected to do their own derivations following the RECIST criteria and then provide the response assessment. Invariably, some errors occur along the way as some tumor burden calculations are in reference to baseline and some are in reference to the nadir e. Since these queries may arrive long after the assessments have been done, investigators may or may not recall all the details why a particular response assessment is given.
The time lag can be overcome by implementing a real time automated response derivation within the EDC so the investigators will get immediate feedback on any derivation errors or inconsistencies with the RECIST. Investigators should be allowed to overwrite the automated response assessment and ideally provide reasons for the discrepancy. We believe such an automated response system implemented in real time will help improve the efficiency of data cleaning and more importantly enhance the quality of the data.
Clinical trials are research studies that aim to determine whether a medical strategy, treatment, or device is safe for use or consumption by humans. These studies may also assess how effective a medical approach is for specific conditions or groups of people. Overall, they add to medical knowledge and provide reliable data to assist in health care decision-making and guidelines. To ensure participant safety, trials start with small groups and examine whether a new method causes any harm or unsatisfactory side effects. This is because a technique that is successful in a laboratory or in animals may not be safe or effective for humans. The main purpose of clinical trials is research. Trials are designed to add to medical knowledge related to the treatment, diagnosis, and prevention of diseases or conditions.
Oncology clinical trials : successful design, conduct, and analysis
Clinical Trials, Second Edition, offers those engaged in clinical trial design a valuable and practical guide. This book takes an integrated approach to incorporate biomedical science, laboratory data of human study, endpoint specification, legal and regulatory aspects and much more with the fundamentals of clinical trial design. It provides an overview of the design options along with the specific details of trial design and offers guidance on how to make appropriate choices. Full of numerous examples and now containing actual decisions from FDA reviewers to better inform trial design, the 2nd edition of Clinical Trials is a must-have resource for early and mid-career researchers and clinicians who design and conduct clinical trials. Researchers, physicians, nurses, pharmacists who plan and run clinical trials, members of the American Medical Writers Association, pharmaceutical and biotechnology industry scientists, pharmacology and pharmaceutical science students, pharmacy students and medical students.
The second edition of Oncology Clinical Trials has been thoroughly revised and updated and now contains the latest designs and methods of conducting and analyzing cancer clinical trials in the era of precision medicine with biologic agents—including trials investigating the safety and efficacy of targeted therapies, immunotherapies, and combination therapies as well as novel radiation therapy modalities. Now divided into six sections this revamped book provides the necessary background and expert guidance from the principles governing oncology clinical trials to the innovative statistical design methods permeating the field; from conducting trials in a safe and effective manner, analyzing and interpreting the data, to a forward-looking assessment and discussion of regulatory issues impacting domestic, international, and global clinical trials. Considered by many as the gold standard reference on oncology clinical trials in the field, the second edition continues to provide examples of real-life flaws and real-world examples for how to successfully design, conduct and analyze quality clinical trials and interpret them. With chapters written by oncologists, researchers, biostatisticians, clinical research administrators, and industry and FDA representatives, this volume provides a comprehensive guide in the design, conduct, monitoring, analysis, and reporting of clinical trials in oncology. About Ovid What's New.
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By Springer Publishing Company. The second edition of Oncology Clinical Trials has been thoroughly revised and updated and now contains the latest designs and methods of conducting and analyzing cancer clinical trials in the era of precision medicine with biologic agents—including trials investigating the safety and efficacy of targeted therapies, immunotherapies, and combination therapies as well as novel radiation therapy modalities. Now divided into six sections this revamped book provides the necessary background and expert guidance from the principles governing oncology clinical trials to the innovative statistical design methods permeating the field; from conducting trials in a safe and effective manner, analyzing and interpreting the data, to a forward-looking assessment and discussion of regulatory issues impacting domestic, international, and global clinical trials.
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