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1. The Clinical Protocol The protocol of each and every study included in an New Drug Application(NDA) or a Biologics License Application (BLA) establishes the foundation on which the entire clinical and statistical sections of the NDA/BLA rest. As a result, each clinical study protocol as part of the overall clinical trial should be carefully planned and well written from the start, taking into bold text consideration advice and feedback from the Food and Drug Administration (FDA) as early as possible in the drug approval process,. If the protocol is poor, no subsequent analysis or report may be able to salvage it or enable the trial to provide pivotal support of an effectiveness claim. Given the importance the clinical protocol has on the overall scheme of drug product development and given the fact that every protocol places the subject at some level of risk, the protocol developer should make every effort to ensure that each protocol written will be able to provide the necessary support for the results of the trial. it is important to note that the protocol document and the sample template from which it is ultimately derived is obtained from multiple sources. In addition to being a companion document to the clinical study report, the protocol derives a good part of its content from federal rules, laws and applicable regulations. 2, Initiating the Protocol Development Process Before the writing of a protocol begins, a good amount of up-front work should have, if already been completed. A "protocol strategy" meeting is the first place to start. The purpose of this meeting and the product that ultimately is derived from it is an analysis plan with text that clearly describes the objectives, variables, trial design including preliminary information on the intended study population (including preliminary exclusion and inclusion criteria). Once an analysis plan has been drafted, several sections can be lifted directly from it for inclusion in the protocol. The draft original source report such as a case report form (CRF) will also be used to drive much of the procedures section of the protocol. It is strongly recommended that each sponsor adopt a template for final report format and content. The final report template should be developed prior to the protocol template. Once the format and content of the final report is known, the protocol is now designed to generate and provide the necessary information for the continuation of the trial. One must keep in mind that, While protocols and final clinical study reports are individual documents that can stand alone meeting separate content requirements, the format and content of these documents should be designed so that the protocol will support the final report. This effort expended in planning the protocol will maximize the value of the final result, including the planned integration of a group of studies into the NDA/BLA. The use of proper formatting formats saves valuable time in writing the final reports, providing the review team with a sense of the organization and professionalism that went into the development of the clinical protocol and the studies that went into the development of a highly accurate and well-structured clinical trial. Standard Protocol Content Recognizing the importance of the protocol, FDA has made a significant effort to explain what information must be included within the document. The minimum criteria are specified in 21 CFR 312.23 (Investigational New Drug Application (IND), which states that any study protocol must contain the following information. (a) A statement of the objectives (b) Purpose of the study (c) The name. address and a statement of the qualifications (CV or other statement of qualification) of each investigator, including the name of each sub-investigator (e.g. medical resident, research associate/postdoc fellow) working under the supervision of the principal investigator; the name and address of the research facilities to be used; and the name and address of each reviewing Institutional Review Board (IRB)/Institution Ethics Committee (IEC). Note: No clinical trial can proceed with the sole approval of an IRB/IEC. (d) The criteria for patient selection and for the exclusion of patients and an estimate of the number of patients to be enrolled. (e) A description of the design of the study, including the type of control group to be used, if any, and a description of the methods to be used to "minimize bias" on the part of subjects, investigators, or analysts. (f) The method for determining the dose(s) to be administered, the safe effective dose, the planned maximum dosage, and the duration of individual patient exposure to the drug. (f) A description of the observations and measurements to be made to fulfill the objectives of the study. (g) A description of clinical procedures, laboratory tests, or other measures to be taken to monitor the effects of the drug in human subjects and to minimize risk and promote benefit to the trial subject/participant. The criteria stated above represent the minimum FDA requirements for a protocol that expose subjects to a test article in clinical trials However, a protocol that meets only these minimum requirements may not be able to provide substantial evidence of safety or effectiveness (efficacy) in support of an NDA/BLA. In addition to these minimum requirements, FDA has established a higher standard of excellence to which clinical trials are expected to conform. In meeting these criteria, the trials must exhibit evidence of having been conducted in a manner deemed “adequate and well-controlled”. The criteria for a study being considered adequate and well-controlled incorporate many of the elements of good science that are not included in the minimum regulatory requirements. For an NDA/BLA to be approved, the sponsor must provide “substantial evidence” of the product’s safety and effectiveness. FDA defines “substantial evidence” as evidence consisting of adequate and well-controlled investigations pursuant to 21 CFR 312.24 (IND Content and Format Content Details). 1) There is a clear statement of the objectives of the investigation and a summary of the proposed or actual methods of analysis in the protocol for the study and in the report of its results. In addition, the protocol should contain a description of the proposed methods of analysis, and the study report should contain a description of the methods of analysis ultimately used. If the protocol does not contain a description of the proposed methods of analysis, the study report should describe how the methods were selected and why the methods of analysis were omitted with strong justification. (2) The study uses a design that permits a valid comparison with a control group to provide a quantitative assessment of drug effect. The protocol for the study and report of the results should describe the study design precisely – for example, the duration of the treatment periods, whether treatments are parallel, randomized, non-randomized, placebo-controlled, sequential, or crossover, and whether the sample size is predetermined or based upon some interim analysis. Generally, the following types of controls are recognized: i. Placebo concurrent control. The test drug is compared with an inactive preparation designed to resemble the test drug to the degree possible. A placebo- controlled study may include additional treatment groups, such as an active treatment control or a dose-comparison control, and usually includes randomization and blinding of patients or investigators or both 2. Dose-comparison concurrent control.in this particular type of situation, at least two doses of the drug are compared. A dose-comparison study may include additional treatment groups, such as a placebo control or active control. Dose-comparison trials usually include randomization and blinding of investigator or patients, or both (i.e., single or double-blind). iii. No treatment concurrent protocol. When objective measurements of effectiveness are available and placebo effect is negligible, the test drug is compared with no treatment. No treatment concurrent trials usually include randomization. iv. Active treatment concurrent control. The test drug is compared with a known effective therapy – for example, when the condition treated is such that administration of placebo or no treatment would be contrary to the interest of the patient. An active treatment study may include additional treatment groups, such as a placebo control or a dose-comparison control. Active treatment trials usually include randomization and blinding of patients or investigators, or both. If the intent of the trial is to show similarity of the test and control drugs, the report of the study should assess the ability of the study to have detected a difference between treatments. Similarity of the test drug and active control can mean either that both drugs were either effective. or neither were effective. The analysis of the study should explain why the drugs should be considered effective in the study – for example, by reference to results in previous placebo-controlled studies of the active control drug. v. Historical control. The results of treatment with the test drug are compared with experience historically derived from the adequately documented natural history of the disease or condition, or from the results of active treatment, in comparable patients. vi. Populations. Because historical control populations are difficult to be well-assessed with respect to pertinent variables similar to concurrent control populations, historical control designs are usually reserved for special circumstances. Examples include studies of diseases with high and predictable mortality (e.g., certain malignancies), and studies in which the effect of the drug is self-evident (e.g., general anesthetics, drug metabolism).(3) The method of selection of subjects provides adequate assurance that the subjects have the disease or condition being studied, on evidence of susceptibility and exposure to the condition against which the prophylaxis directed.

(3) The method of assigning patients to treatment and control groups minimizes bias and is intended to assure comparability of the groups with respect to pertinent variables such as age, sex, severity of disease, duration of disease, and use of drugs or therapy other than the test drug. The protocol for the study and the report of its results should describe how the subjects were assigned to study groups. Ordinarily, in a concurrently controlled study, assignment is, not by randomization, nor is without stratification. (4) Adequate measures are taken to minimize bias on the part of the subjects, observers, and analysts of the data. The protocol and report of the study should describe the procedures used to accomplish such, such as blinding and masking. (5) The methods for assessing subjects’ responses are well defined and reliable. The protocol for the study and the report of the results should explain the variables measured, the methods of observation, and criteria used to assess response. (7) There is an analysis of the study results adequate to assess the effects of the drug including any appropriate statistical methods and development of optimal statistical power and statistical significance. The analysis should assess, among other things, the comparability of test and control groups with respect to pertinent variables and the effects of any interim data analyses performed. As it is obvious from the above requirements, the protocol and final study report are intended to be companion documents that contain much of the same information. How does one differ from another: A protocol states how a study is to conducted and provides the means for obtaining pre-determined information for the analysis and final report of a clinical trial. The final report, on the other hand, states exactly" how well the protocol was followed," and presents the results of the study. Much of the final report’s content should be included in the protocol to enhance the support that the protocol provides for the final report. The use of similar content also aids the process of writing the final report, since it allows the author to copy much of the information from the protocol directly into the final study. going back to a Phase 1 (IND, safety) studd that takes into account as many of the adequate and well-controlled criteria as possible, the developer can be assured that the data more accurately evaluates the product’s safety (and preliminary effectiveness if that is what being's analyzed along with the primary end point, safety). Regarding the risk-to-benefit ratio, a trial that places subjects at risk, yet cannot provide accurate and dependable results, should not be conducted. Any trial lacking the potential to significantly expand the scientific knowledge bae regarding a product places subjects at risk. It is important to note that, in some cases, an adequate and well-controlled trial may simply not be feasible early in Phase I. All trials, however, should be designed to include as many criteria as possible/necessary for an “adequate and well-controlled” study. Standard Protocol Format The standard content adopted for all protocols should be contained in a standard format. The format’s purpose should be to present the required content of the protocol in an easily readable, user-friendly manner. Information should be divided into sections and subsections, with logical grouping of related information clearly identified through the use of indicative headings. Additionally, the protocol’s general format should be identical to that of the study report template. Whenever possible, the information that is contained in both the final study report and the protocol should be contained in the same section or subsection, and under the same headings within both documents. Many protocol sections are nearly identical to those in the final report. Most of the information in the protocol is also used ins some form within the protocol. The use of similar formatting in the protocol and the final report enhances and emphasizes the shared content of the documents, and is an indication of the planning involved throughout the design, conduct and report of a clinical trial. The standard protocol format should contain the same major structural elements as the clinical study report. Each of these contents include: Title Page Table of Contents. The table of contents (TOC) main purpose is to provide a listing of, and a location for, the protocol’s sections and subsections. Ideally, the TOC should be generated automatically in word format. All sections and subsections of a TOC are neatly arranged in a coherent, logical sequence. Related information is grouped within sections and subsections under indicative headings. While the overall standard format should be utilized for every protocol, each protocol will vary considerable in the content of certain sections due to the study-specific details of the trial. Therefore, the numbering scheme selected for the protocol allows for compartmentalization of information and flexibility within the established format. For example, Section 3.6 contains a description of the procedures to be followed during each study visit. While the number of visits and procedures will change from study to study, any number of subsections can be added to the section by numbering them 3.6.1, 3.6.2 etc. In this way, there is flexibility within a protocol without having to change the overall numbering scheme, thereby maintaining the format’s integrity. Body of the Text. The body of the protocol should contain all of the information required by federal regulations, relevant FDA guidances, information from public hearing, advisory committee meetings or publications, and the developer’s final report template. It is the author’s responsibility to ensure that each topic is covered in such a manner that all regulatory requirements are met, and that the investigator and staff members can clearly understand the instructions given. Protocol Summary After the body of the text has been written, the authors should prepare a brief summary of the study’s major characteristics. By providing a protocol summary, the authors allow the reader to gain a general knowledge of the study by glancing at just a few pages.The FDA is well aware of the benefit of a protocol summary, and has requested that each protocol included in an NDA/BLA attach a protocol cover sheet identifying many of the same study characteristics included in the summary. In addition, the protocol summary can aid as a review tool, and is often a way to familiarize the potential investigators with the study plan. While a protocol summary can be arranged in a number of ways, the information included in the summary should be consistent across all summaries. The recommended protocol summary contains the following elements: 1) The title of the study (identical to the title page); 2) The clinical phases; 3) The name, medical specialty, institutional affiliation and address of the principal investigator; 4) The period of the trial (projected dates of enrollment of first subject to completion of last subject); 5) Study objectives; 6) Study variables; 7) Design; 8) Inclusion criteria 9) Exclusion criteria 10) Number of subjects to be enrolled, then listed for each test article, along with a description of the test article(s); 11) The duration of the therapy; 12) Any reference product and its dosing regimen. For a multicenter study, the investigator section should state “multicenter” and a list of investigators pages should be added after the summary. As is evident from the recommended contents, a reader will be provided with most of the vital study information in just a few pages. The protocol summary is usually placed immediately after the table of contents. As part of the protocol summary, it is often helpful and advisable to include a study flow chart incorporating a time and event table to illustrate the study design. If possible, the study flow chart is recommended to be one page for easy review by the reviewer. A study flow chart is also included in the sample protocol. The study flow chart should illustrate the periods of the study (e.g., baseline placebo, double-blind, open label) in chronological order. The time and events table should illustrate the major measurements to be made or procedures to be followed at each division within the study (e.g., screen, baseline, study date number etc.). All of the measurements/procedures on this table should be consistent with the procedures section of the protocol. Standard Protocol Template For each protocol to conform to the standard protocols' format and content, these elements should be combined into a standard protocol template which is a full protocol outline organized in a clear, easily-readable format. The standard protocol template should be used when writing each new protocol. The use of a standard protocol template will provide the following benefits.

1. Following a standard template provides the best assurance that no details will be overlooked. The protocol is a document that addresses every element of how a study is to be carried out in extremely specific detail. This detail is essential to ensure uniform compliance with the requirements of the protocol. However, the protocol should not be so specifically devised as to make its implementation difficult on a practical basis. Details that are unnecessarily restrictive may lead to protocol violations or significantly impede enrollment and the conduct of the trial. The end result shouldd be a realistic but detailed document that can be implemented by the investigator and their staff during the clinical study. The use of a standard protocol template organizes all of this necessary information in a consistent format, resulting in a detailed, complete and professional looking protocol. 2. Since the standard protocol template will be used for every protocol, the authors of each new protocol need only follow the adopted format and content of the template. Without a standard format or content, the authors of each new protocol would have to decide upon the information that should be included in the protocol and then develop some format to accommodate that information into the protocol. In essence, the authors of each new protocol would “reinvent the wheel”. This method of developing protocols is unnecessarily difficult. The use of a standard protocol template frees the authors from format and content considerations, allowing them to focus their efforts on designing a safe and efficient protocol. 3. Many protocol sections contain information that is vital to its eventual usefulness in supporting an NDA or a BLA. The use of reliable and generally accepted methods and procedures in the protocol will provide a strong foundation upon which to make conclusions about the clinical trial’s success. Employing a standard protocol template will ensure that every protocol will contain the following: elements associated with “good science”, such as blinding and randomization; safety features such as definitions of serious adverse event(SAE), serious adverse experiences and procedures for reporting SAEs; and quality control issues involving data collection and ensuring data integrity. The result is that each protocol developed from the standard template will employ the same sound methods, thereby maximizing both the safety of the subjects participating in the trial and the validity of the results. 4. Establishing a uniformity in format and content makes the job of study personnel, and especially an FDA reviewer much easier. furthermore, using a standard protocol results in a protocol that is very similar. Information contained in a particular section or subsection in one protocol will be contained in the same place in every other protocol. This arrangement enables a reader, as well as the reviewer to find information quickly and easily among any number of protocols and, therefore can be of particular benefit during an FDA review. FDA reviewers will look across trials, particularly at those of similar design. Therefore, the FDA reviewer will want to compare protocols for similar characteristics or design features. The use of a standard protocol template will facilitate these comparisons and aid the reviewer. Drafting an Individual Study Protocol. After the template’s table of contents, body, and summary have been designed and adapted, the developer is ready to begin writing protocols for the anticipated clinical trials. Since the key elements of a protocol are the clinical and statistical design features, the clinical monitor, site personnel, clinical research associates, clinical trial managers and biostatistician should be the primary authors. If the protocol template has been designed correctly, the authors need only to follow the content cues of each section and subsection and fill in the necessary information. When writing the protocol, the authors must keep in mind the protocol’s purpose. The protocol is a means for generating pre-defined information for the analysis and final report of a clinical trial. This information will have been identified based upon the anticipated content of the NDA/BLA, the anticipated content of the final report, and the analysis plan and CRFs. The entire process of planning works backward to the protocol. The protocol is then designed to provide all of the pre-defined information, which is then collected, analyzed and presented in a predetermined manner. Conclusion In the event of clinical development, the protocol is crucial in establishing a proper foundation for the conduct of a study and its analysis and report. The study objectives and, in particular the study variables must be clearly defined to eliminate any ambiguity or misinterpretation. The procedures and methods sections must adequately describe the manner in which the study is to be conducted. Finally, the statistical methods and analyses section must predefine the crucial studies to be conducted at the study’s completion to evaluate and safety and effectiveness. Benefits of a master protocol design. Through an over-arching infrastructure, trial design, and protocol with multiple subs-studies, varying protocols can be run simultaneously. further, a master protocol is intended to run continuously to evaluate and assess a single investigational drug or multiple indications or patient populations, or multiple drug candidates for the same indication. Over the past few years, FDA has been encouraging sponsors of clinical development programs in areas such as oncology and pediatrics to use a master protocol approach to expedite and streamline mid-to-late stage drug development. If well executed, a master protocol approach can reduce study overhead. cost incursions, redundancies and duplication of activities, reduce patient exposure to control arms through use of a single control arm, and most importantly, generate data to address multiple questions regarding the safety and efficacy of drug candidate(s) in parallel rather than sequentially. Master Protocol Implementation Challenges Planning, executing and monitoring the simultaneous sub-studies under a master protocol require a great deal of coordination and the appropriate trial infrastructure, so a sponsor has to have sufficient resources and well-trained personnel. For example, the draft guidance notes that sponsors should have medical monitors with appropriate training and experience in the conduct of clinical trials and the indications under study, given the potential for rapid patient accrual with increased risk to patients if adverse events are not properly identified. Furthermore, FDA acknowledges that one of the challenges for master protocols is related to assessment of safety of the investigational product(s) under the protocol. With multiple arms assessing a single product across multiple patient population, there could be difficulty in attributing adverse events appropriately to the investigational drugs. FDA also cautions that multiple study groups under a master protocol could result in an over-interpretation of findings, such as falsely identifying a responder population based on multiple between-arm comparisons. Therefore, sponsors should carefully consider the potential advantages and challenges to determine whether a master protocol is appropriate.