Topic: Protocol Feasibility
Please write a 4-page (double spaced) paper (high level masters paper) answering the following two questions in detail:
1. Explain the process of reviewing a protocol and determining protocol feasibility.
2. What do you think some barriers might be to figuring out whether a protocol is feasible or not?
**Please utilize the following attached PDF’s & YouTube videos, which is requirement of the paper**
https://www.youtube.com/watch?v=4_t5Ks8cDF0&t=2s
https://www.youtube.com/watch?v=r6Gpv0oqxEk
https://www.youtube.com/watch?v=xa-QMyDHKE8
https://www.youtube.com/watch?v=-hWo8rqsWYQ
https://www.youtube.com/watch?v=fpQj0jdmMEk&t=2s
https://www.youtube.com/watch?v=TAvLWXTGciA
https://www.youtube.com/watch?v=QSI9576c7ag
The Protocol The Protocol In this Chapter Understanding the common components of a protocol: n Objectives and endpoints n Randomization types and methods n Statistical considerations 9 “The beginning is the most important part of the work.” Plato (427 BC–347 BC), Greek author and philosopher A Clinical Trials Manual From The Duke Clinical Research Institute: Lessons From A Horse Named Jim, 2nd edition. By Margaret B. Liu and Kate Davis. Published 2010 by Blackwell Publishing 9781405195157_4_C09.qxd 11/16/09 15:27 Page 177 A Clinical Trials Manual from the Duke Clinical Research Institute: Lessons From A Horse Named Jim, Second Edition Margaret B. Liu and Kate Davis © 2010 by Duke Clinical Research Institute. ISBN: 978-1-405-19515-7 The protocol is a document that provides the background and frame- work for the planned study and describes how it will be implemented. Protocols are written by trial sponsor personnel, individual investiga- tors, clinicians, scientists, or any combination of these individuals. Protocol authors often solicit input from prominent experts, practicing clinicians, and biostatisticians to ensure the protocol is clinically relev- ant and that the design is sufficiently statistically rigorous to meet its stated objectives; is practical for sites to enroll subjects; and can be completed in the proposed time frame. Many trials have a Steering Committee (a group of experts in the area of study) that is responsible for the oversight of a proposed trial or group of trials. Steering Com- mittee members often contribute to protocol design, providing input on clinical issues, subject safety, and statistical matters. Protocols can vary greatly in writing style, content, and flow; all, however, should provide the individual investigator with a thorough understanding of the goals of the study and the procedures involved. Depending on the written discussion of the background work and previous trials conducted, the complexity of the trial, required pro- cedures, and many other factors, protocols may range in length from one or two pages to more than 100 pages, with 40–60 pages being a typical length. In the United States, the trial sponsor submits the final protocol to the U.S. Food and Drug Administration (FDA) as part of an Investigational New Drug (IND) application or Investigational Device Exemption (IDE) application. The FDA must approve the protocol before the sponsor can initiate the clinical trial at the investigative sites. Not all protocols, however, require FDA review and approval. Protocols for clinical investigations of marketed drugs, protocols that are post-marketing (phase 4), and observational protocols (that is, there is no investigational product under study) do not need FDA approval before starting the trial; they do however require Institu- tional Review Board (IRB) approval. Protocols for clinical investigations of marketed drugs do not require submission of an IND application if all of the following con- ditions are met: 1 Study data will not be reported to the FDA in support of a new indication for use or to support any other significant change in drug labeling. 2 The drug undergoing investigation is lawfully marketed as a pre- scription drug and the study data are not intended to support a significant change in the product advertising. 3 The study does not involve a change in the route of administra- tion or dosage level or use in a patient population or other factor 178 9781405195157_4_C09.qxd 11/16/09 15:27 Page 178 179 9. Th e Pr o to co l that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product. 4 The study is conducted in com- pliance with the requirements for IRB review (21 CFR 56) and informed consent (21 CFR 50). 5 The study is conducted in com- pliance with the requirements con- cerning the promotion and sale of investigational drugs (21 CFR 312.7). 6 The study does not intend to invoke exception from informed consent requirements for emergency research (21 CFR 50.24).1 Regardless of whether FDA approval is required, investigators must submit the protocol to their IRB for review and approval. It is the role of the IRB to review the protocol in the context of the local patient population to deter- mine whether the study design is scientifically valid, has an acceptable benefit-to-risk ratio for subjects, and the proposed subject selection is fair and equitable. The IRB also reviews the informed consent process and docu- ment, and seeks to ensure protection of subject privacy and data confidentiality. IRB approval must be granted before a clinical trial can be started at the inves- tigative site. If changes to a protocol for an IND or IDE study are indicated after initial FDA approval is obtained, the authors must write a protocol amendment and sub- mit it to the FDA. IRBs must review and approve amendments before the changes to the protocol can be imple- mented. Once a protocol is finalized and approved, it becomes the final authority on enrollment criteria and One example of a study that did not require an IND application is the BRIDGE (Bridging Anticoagulation in Patients who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive ProceDure or SurGEry) study. Warfarin is an oral anticoagulant commonly used to prevent stroke or thromboembolism in patients with chronic health conditions, such as atrial fibrillation, artificial heart valves, and previous venous or pulmonary thromboembolism. When patients on warfarin require surgery or other procedures, warfarin is typically stopped 5 days before the procedure or surgery to minimize the risk of bleeding. The goal of the BRIDGE study is to compare bridging anticoagulation with “no bridging therapy” in patients with atrial fibrillation, and in doing so, establish a standard of care for patients who require temporary interruption of warfarin due to a procedure or elective surgery. To determine the risk of thromboembolus and bleeding complications, study subjects are randomized to receive either previously- marketed anticoagulants or placebo to bridge the time between pre- and postoperative warfarin therapy. Because the study met all of the conditions in 21 CFR 312.2(b)(1), the protocol did not require an IND application or FDA approval, but did require informed consent of subjects and was registered with ClinicalTrials.gov, a government Web site that provides information about clinical trials. Implementation of protocol-required procedures at the site In some situations, site staffing or personnel issues dictate how study-required procedures will be implemented. For example, one site may have hospital laboratory personnel available to obtain protocol-required blood samples and perform the centrifuging, labeling, and freezing of the specimens, while at another site the Clinical Research Coordinator (CRC) may be responsible for performing these tasks. In other situations, logistical issues at the site may determine how protocol-related procedures are completed. For example, in a study where subjects are enrolled in the emergency department and must receive study drug within a short time after randomization, a hospital with a 24-hour pharmacy near the emergency department may store study drug in the pharmacy. However, an institution without a convenient pharmacy or 24-hour pharmacy staff may require study drug to be stored in a secure location within the emergency department. 9781405195157_4_C09.qxd 11/16/09 15:27 Page 179 study procedures. While investigative sites may employ site-specific methods when implementing the study, specific eligibility criteria and study- required procedures must be followed carefully. Common Components of a Protocol Protocols come in many styles and sizes depending on the study phase, the type of product under investigation, and many other factors. In addition to collecting data to answer the primary research question(s), the protocol design must also ensure that regulatory requirements are met, including informed consent, reporting of adverse events (AEs), and protocol adherence. Background and Rationale The background section of the protocol includes results from pre-clinical studies and previous clin- ical trials. A description of the disease or disorder may be included and adequate information per- taining to safety and efficacy demonstrated in previous studies should be provided. The rationale for the study should clearly state the reason the trial is being conducted and should be consistent with the background information provided. Study Organization The organizational structure of the study is based on protocol needs, financial considerations, and logistical issues presented by the study design. Most protocols identify the groups and/or indi- viduals who will manage various study activities, including site management, monitoring, safety reporting, test article distribution, and data 180 Protocol Design Resources A number of good protocol-design resources, including protocol templates, can be found online at the National Institutes of Health (NIH) Web site and at the Web site for Cancer Therapy Evaluation Program (CTEP), part of the National Cancer Institute (NCI). Several of the National Institutes have their own more specific protocol templates as well (e.g., the National Institute of Allergy and Infectious Diseases).2 Please refer to Appendix E for protocol design resources. Sample Table of Contents for a Protocol Introduction Background Rationale Previous Animal/Human Studies Objectives Endpoints Trial Design Subject Selection Randomization Treatment Plan Schedule of Assessments Test Article Preparation, Packaging, and Labeling Dosing Schedule Storage, Dispensing, and Disposal/Return Accountability Records Data Collection Adverse Event Reporting Statistical Analysis Ethical Considerations Informed Consent Confidentiality Benefits/Risk of Harm Inclusion of Women, Children, and Minorities Monitoring Subject Compensation Publication of Results 9781405195157_4_C09.qxd 11/16/09 15:27 Page 180 181 9. Th e Pr o to co l Examples of Endpoints Single Endpoints Death Stroke Rehospitalization Quality of life parameters Economic factors Tumor regression/tumor size Composite Endpoints All-cause death or MI or stroke All-cause death or hospitalization or cardiac arrest All-cause death or end-stage renal disease or doubled serum creatinine management. The use of central or core laboratory facilities should also be noted. Objectives/Endpoints The objectives of the study are often stated as primary and secondary endpoints (variables). Endpoints are measures believed to quantify the potential effect of a treatment or therapy under study. In addi- tion to clinical endpoints, quality of life and economic factors may also be identified as endpoints. A clinical endpoint should be: 1 Relevant and easy to interpret; 2 Clinically apparent and easy to identify; and 3 Sensitive to treatment differences. Endpoints can be single or composite. A single primary endpoint might be undesirable in circumstances where clinically important events are rare and the treatment has an effect on a variety of important endpoints. Composite endpoints are commonly used in randomized controlled trials (RCTs) because they offer potential advantages, such as smaller sample sizes and shorter completion times. However, composite endpoints are also associated with certain risks, particularly if basic clinical and statistical requirements are not adequately respected. Difficulties in interpretation arise when the results of single components of the composite endpoint go in opposite directions, as well as when hard clinical outcomes are combined with soft endpoints, particularly if the latter occur much more frequently but are of lesser relevance. Accordingly, all indi- vidual components of the composite endpoints may require analysis using statistical techniques that use multiple testing and/or close testing procedures. Quality of Life Parameters The study of quality of life (QOL),