Each clinical trial has a master plan called a protocol. The protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations, and organization of the planned trial. The protocol is a document used to gain confirmation of the trial design (see draft strategy guide) by a panel of experts and adherence by all study investigators, even if conducted in various countries. Details of the trial are also provided in other supporting documents referenced in the protocol, such as an investigator’s brochure (IB) [21 CFR 312.23(a)(5)],pharmacy guide [21 CFR 312.23(a)(8)], laboratory manual, safety monitoring plan, study monitoring plan, data management plan, statistical analysis plan, and quality assurance plan.
The Protocol is a required document for submission of an IND, along with the: cover sheet, table of contents, introductory statement, investigational brochure (IB), chemistry, manufacturing, and control information, pharmacology and toxicology information, previous human experience, additional relevant information.
The protocol contains a precise study plan for executing the clinical trial, not only to assure safety and health of the trial subjects, but also to provide an exact template for trial conduct by investigators at multiple locations to perform the study in exactly the same way. This harmonization allows data to be combined collectively as though all investigators (referred to as “sites”) were working closely together. The protocol also gives the study administrators (often a contract research organization), as well as the site team of physicians, nurses and clinic administrators, a common reference document for site responsibilities during the trial. Investigators and Sub investigators (as declared on the form FDA-1572, FDA Info FAQ Guide on 1572) are selected by the sponsor per part 312.53, and “monitored by qualified by training and experience to monitor the progress of the investigation”.
The format and content of clinical trial protocols sponsored by pharmaceutical, or biotechnology companies in the United States, European Union, or Japan have been standardized to follow Good Clinical Practice guidance issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Regulatory authorities in (Health) Canada and (Department of Health) Australia also follow ICH guidelines.
Protocol changes once approved by the FDA may require amendment depending on the change [21 CFR 312.30], especially anything that “significantly affects the safety of subjects”.
Protocol amendments section outlines impacting events within the life cycle of a protocol that would require an amendment of that protocol to be submitted for review.
Eligibility Criteria: The protocol describes what types of patients are able to take part in the research—that is, who is eligible. Each trial must include only people who fit the patient traits for that study (the eligibility criteria). Eligibility criteria differ from trial to trial. They include factors such as a patient’s age and gender, the type and stage of disease, and whether the patient has had certain treatments or has other health problems. Eligibility criteria ensure that new approaches are tested on similar groups of people. This makes it clear to whom a clinical trial’s results apply. These criteria also are a safety measure. They ensure a trial excludes any people for whom the protocol has known risks that outweigh any possible benefits. Researchers may be tempted to select trial subjects who are most likely to do well on an experimental therapy. In addition, trials are regarded as “cleaner” if they eliminate any potentially confounding factors that could affect the study’s outcome. Concurrent use of other medications is also often excluded because they might interact with the experimental agent, potentially impairing its activity or causing unforeseen side effects. Another common exclusion criterion is active substance use, since many researchers assume that alcohol and illicit drug users have chaotic lives and are less likely to achieve optimal adherance.
Endpoints: These include milestones, ideally specified before a study begins, that an experimental agent must achieve or bring about in order to be considered a success. Traditionally, trials have employed clinically meaningful endpoints, for example, disease resolution, progression disease, or death.
Clinical Trial Phase: Clinical trials are done in phases that have different purposes and help researchers answer different questions. Each phase of the drug approval process is treated as a separate clinical trial. The drug-development process will normally proceed through all four phases over many years. If the drug successfully passes through Phases 0, 1, 2, and 3, it will usually be approved by the national regulatory authority for use in the general population. The number of subjects in a trial is a critical factor in determining a drug’s efficacy, as well as influencing the study’s perceived credibility. While it may take only a few subjects to uncover major toxicities, many more participants are needed to determine conclusively that an agent works. With a small number of subjects, there is always the possibility that an outcome could be the result of chance rather than being a true effect of an experimental therapy. Researchers, therefore, try to include enough subjects in their trials so that the results will be considered statistically significant, or very unlikely to be due to chance alone. The ability of a study to produce statistically significant data is known as its power.
Comparison Groups: In most clinical trials, researchers use comparison groups. This means that the patients taking part in a trial are assigned to one of two or more similar groups. Each group will receive different medical strategies. Using comparison groups also ensures that no one in a study is left without treatment for the sake of research. Sometimes, when no accepted standard treatment exists for a condition, people in one group may receive a placebo.
Randomization: Most clinical trials that have comparison groups use randomization. This involves assigning patients to different comparison groups by chance, rather than choice. This method helps ensure that any differences observed during a trial are due to the different strategies being used, not to preexisting differences between the patients. Usually, a computer program makes the group assignments.
Masking: The term “masking” refers to not telling the clinical trial participants which treatment they’re getting. Masking, or “blinding,” helps avoid bias. For this reason, researchers also may not be told which treatments the patients are getting. However, trial records can quickly show this information if safety issues arise.
Administration: Clinical trials designed by a local investigator, and (in the US) federally funded clinical trials, are almost always administered by the researcher who designed the study and applied for the grant. Clinical trials of new drugs are usually administered by a contract research organization (CRO) hired by the sponsoring company. The sponsor provides the drug and medical oversight. A CRO is contracted to perform all the administrative work on a clinical trial. For Phases 2, 3 and 4, the CRO recruits participating researchers, trains them, provides them with supplies, coordinates study administration and data collection, sets up meetings, monitors the sites for compliance with the clinical protocol, and ensures the sponsor receives data from every site. However, ultimate responsibility always is that of the sponsor.
At a participating site, one or more research assistants (often nurses) do most of the work in conducting the clinical trial. The research assistant’s job can include some or all of the following: providing the local institutional review board (IRB) with the documentation necessary to obtain its permission to conduct the study, assisting with study start-up, identifying eligible patients, obtaining consent from them or their families, administering study treatment(s), collecting and statistically analyzing data, maintaining and updating data files during followup, and communicating with the IRB, as well as the sponsor and CRO.
Paying for Clinical Trials: There are two types of costs associated with a clinical trial: patient care costs and research costs. Patient care costs are those costs related to treating your cancer, whether you are in a trial or receiving standard therapy. These costs are often covered by health insurance. They include: Doctor visits, Hospital stays, Lab tests, X-rays and other imaging tests. Research costs are those related to taking part in the trial. Often these costs are not covered by health insurance, but they may be covered by the trial’s sponsor. Examples include: The study drug, Lab tests performed purely for research purposes, Additional x-rays and imaging tests performed solely for the trial. When you take part in a trial, you may have extra doctor visits that you would not have with standard treatment. These extra visits can add costs for transportation and child care.
Efficacy and safety Assessments: Specification of efficacy and safety parameters and the identification of methods, timing, for assessing, recording and analyzing specified parameters. Defining adverse events (AE) and serious adverse events (SAEs). The procedures for recording and reporting AEs and SAEs. Defining the follow-up duration. Reporting of any deviation from the protocol. Description of data and safety monitoring plan, including assessment and reporting to IRB, FDA, etc. Identify if the plan will involve an independent medical monitor, data monitoring committee, and/or data and safety monitoring committee.
Statistical Analysis: Description of statistical methods to be utilized, including timing of interim analysis if appropriate. The number of subjects to be enrolled, along with rationale for sample size (power calculation and clinical justification). Level of significance to be used. The selection of subjects to be included in the analysis (valuable subjects).