How to write a protocol guideline

Guidelines for protocol manual is intended to be a guide for investigators and other clinical staff at all levels of experience to the development, approval, and conduct of a protocol in the warren grant magnuson clinical center of the national institutes of health (nih). This manual describes the steps necessary to design a good clinical protocol; defines the review process needed to ensure scientific validity, ethical merit, and other hallmarks of good research; and outlines the process of managing a study using the protocol and other research tools. Moreover, the increasing complexity of the research itself also affects the process of designing and managing al research term "protocol" is defined as a complete written description of, and scientific rationale for, a research activity involving human subjects. In the context of this manual, "protocol" means both the written description of the research activity and the activity itself. Through protocols, investigators find new and better ways to help prevent, detect, diagnose, control, and treat a wide variety of principal principal investigator (pi) is the individual responsible and accountable for designing, conducting, and monitoring a protocol. The pi must assure that the protocol is followed and the data collected promptly and accurately. Specific responsibilities of a pi include writing the protocol document, assuring that necessary approvals are obtained, monitoring the protocol during its execution, and analyzing the manual presents the rudiments of the art of bringing a protocol into actual practice. Any investigator desiring sound, professional advice on protocol matters should seek the expertise of his or her clinical director, branch chief, or department head. These individuals are the most knowledgeable about the subject matter that interests the investigator, and they "know the system," as they also have served as pi's on many protocols. As investigators delve into the intricacies of their protocols, they may find it necessary to consult with other specialists who can contribute to the protocol design. For example, a protocol may require special x-rays, rehabilitation measures, ethical considerations, apheresis of white cells, surgical interventions, or complex medication forms with rigid rules for igators will find that successful clinical research involves much more than scientific considerations. The commission was charged with defining the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects and with developing guidelines to assure that research is conducted in accordance with those principles. A basic premise guiding the commission was that each clinical research protocol represents a partnership among the pi, the other members of the research team, and the subjects who volunteer for the protocol.

Define research protocol

It is therefore of the utmost importance that research carried out at the cc be designed and conducted with the highest regard for the rights and welfare of human result of the panel's work is "the belmont report: ethical principles and guidelines for the protection of human subjects of research. Approved by the secretary of the department of health, education, and welfare (now the department of health and human services [dhhs]) in april 1979, "the belmont report" is a statement of basic principles and guidelines of the ethical issues that surround the conduct of research with human subjects. Mpa's must be renewed every 5 a foreign institution or a domestic site that does not hold an mpa is about to receive dhhs funding for a single clinical research protocol involving human subjects, or intends to collaborate with an institution that receives dhhs funding, that institution must negotiate a "single project assurance" (spa). Collaborative activities by the nih investigator could include examining patients, collecting specimens, visiting institutions to perform research or clinical work, supplying reagents, performing tests, analyzing data, exchanging data containing personal identifiers or potential identifiers (such as codes), performing preliminary data-collection activities involving human subjects, or substantively contributing to research technique, protocol design, or interpretation of all collaborations are defined in advance. Some may develop during the course of a protocol, and an objective third-party review may be necessary to determine whether a collaboration exists. Pi's and irb chairs who are unsure about requesting negotiation of an spa are encouraged to contact ohsr for inary thoughts on writing a s the first thing an investigator needs when developing a protocol is a testable hypothesis. Protocols that require outpatients to return to the clinic or later be readmitted to the hospital, the pi should consider the steps to be taken when a participant fails to keep an appointment. In many protocols, a week or two on either side of a scheduled data collection point is perfectly acceptable, but in other protocols some step must be taken within hours of a designated time. The pi should specify these "tolerances" in advance and tightly maintain them through the the protocol involves drawing blood frequently, lengthy infusions, or close monitoring of the patient, the pi should explore the option of using one of the cc's several day hospitals rather than an inpatient admission. The head nurses of the day hospitals are good sources of further r matter for the pi to consider in advance is a plan for ending the protocol. If each patient has a defined "end of study," the investigator may have subjects completing their participation in the protocol over several years or even longer. Unmasking is one of the areas in the protocol design that the pi should thoroughly review with a statistical last part of the study preparation is writing up the clinical research process, i. The protocol must be legible and commonly is prepared on a computer, which makes it easier to track the many revisions and is also a good time for the pi to think about the future report of the study results.

It is wise to reach some sort of understanding with potential authors about who will write the first draft and the order of names on the finished manuscript; sadly, unsettled points like these can later create hostilities. The authorship issue is discussed briefly in "guidelines for the conduct of research in the intramural research program at the nih," a booklet with which one should become familiar. Copies of the booklet can be obtained from the office of the al research protocol: initial review nih-1195, "clinical research protocol: initial review application" (figure 1), captures and summarizes considerable information about the proposed protocol, including the title, multisite collaboration, accrual exclusions and characteristics, radiation use, and associate investigator participation. Form nih-1195, placed at the forefront of the initial review application package, is designed to carry the protocol through the entire review process. The prospective pi prepares the 1: nih-1195 -- clinical research protocol: initial review here to download following sections describe each of the data items on the "clinical research protocol: initial review application" form:The principal investigator is the individual responsible and accountable for designing, conducting, and monitoring the protocol. When a pi is not a member of the junior or senior staff, or when a clinical director, irb, or the cc director considers it warranted, a medical advisory investigator must be assigned to the protocol (see "medical advisory investigator"). Consultants and students may not serve as pi's or as medical advisory investigators on protocols. The pi's full name, professional designation and degree, institute and branch affiliation, nih address, and telephone number must be identified on the nih-1195 protocol title is the name of the study. It should be easy to remember, recognizable by administrative support staff, and sufficiently different from other protocol titles to avoid confusion. Brevity with specificity is the key, and comprehensiveness definitely comes in abbreviated title is a shorthand title for the protocol that can be listed in the appropriate indices of the mis to make protocol identification easier for the investigator. Protocols with end points such as the appearance of renal failure or myocardial infarction would be of indefinite duration, unless a date is specified for ending all follow-up. Duration also has been defined as the time during which new subjects are entered into the protocol (see "determination of sample size"). A prospective research participant may be interested in duration when it is defined as the time he or she will be active in the protocol.

Of course, some protocols use death as an end point; these may stretch over many nih, the duration of a protocol is the length of time required to enroll subjects and to complete the protocol to the point at which subjects are no longer involved. If the protocol's continuing reviews are up to date, a protocol is considered active until the pi notifies the irb or the ohsr that he or she has completed the protocol. Note that protocols often exceed their expected duration because suitable subjects are not accrued as rapidly as initially total subjects to be accrued indicates the maximum number of subjects the pi anticipates enrolling in the protocol. Any adjustments to the accrual ceiling after initial approval by the irb must be reviewed and approved by the ite collaboration indicates whether or not the protocol entails participation from another domestic site, a foreign site, or both. If the protocol involves multisite collaboration, the full name and address of each site or institution must be given on a separate sheet of paper, together with each institution's mpa number, if ted accrual exclusion reflects the category(ies) of people the pi requests to exclude from the study population. If these groups are to be excluded from the protocol, the application or proposal must contain a clear and compelling rationale and justification to the irb for such an exclusion. More than one box may be checked in this t accrual characteristics categorize the makeup of the protocol's study population to assist in future planning for resource age reflects the age range of the majority of the participants to be enrolled on the protocol. Only one box should be checked in this ric is the age range of child subjects to be enrolled on the protocol. More than one box may be checked in this ed refers to physically and/or cognitively impaired subjects to be enrolled on the protocol. Only one box should be checked in this eer categorizes the type of volunteers to be enrolled on the protocol. More than one box may be l or healthy clinical research volunteer: healthy clinical research volunteers are typically residents of the local community who respond to advertisements in the media or visit the clinical research volunteer program (crvp) office and review information about protocols that need healthy volunteers. Requests for student volunteers should be submitted to the employee: nih employees may volunteer for protocols under rather strict regulations. Physicians or others wishing to enter their own protocols may do so if they are properly registered as patients, undergo the protocol-required preliminaries, and sign the protocol consent document(s).

Nih employees must use personal leave to participate, but they may still receive patient: an individual with a disease or disorder who is participating in a protocol studying that disease or disorder may volunteer for other eer compensation: the pi must determine and then describe in the protocol the compensation that healthy clinical research volunteers will receive for time and inconvenience while participating on the protocol in addition to the compensation, if any, they will receive for travel and escort needs. Only one box should be checked in this l resource requirements identifies high-profile resources in limited supply necessary to carry out the protocol, for example, intensive-care services. Early identification of these resources allows cc departments to plan in advance for these services and, if necessary, expand early in the process to accommodate the protocol. More than one box may be checked in this ds are used to enable computer users to search for the protocol's salient features not included in the protocol title. A maximum of 10 primary keywords or phrases, excluding those found in the protocol title, should be ol types: each protocol is assigned to one of the four intramural clinical protocol types: screening, training, natural history, and clinical ing protocols are designed to determine if individuals may be suitable candidates for nih protocols. Specific screening protocols may be written for long-term accrual of cohorts of patients with interesting, unexplained disease presentation for the purpose of identifying new syndromes. A patient may be carried on a screening protocol for a maximum of 12 consecutive months, at which time one of three things may occur: 1) the patient is re-enrolled on the screening protocol, thus requiring a new protocol consent document to be signed; 2) the patient is transferred to an active clinical trial, natural history, or training protocol; or 3) the patient is removed from the screening protocol and made inactive. The projected number of patients to be accrued to such screening protocols must be estimated in advance and subsequently ng protocols allow staff physicians and other health care workers to follow particular types of patients in order to maintain or improve their professional skills. The projected number of subjects to be accrued to a training protocol must be indicated in advance on the form and subsequently l history/disease pathogenesis protocols are designed to study normal human biology and disease pathogenesis. Such protocols may have multiple components, including provisions for screening, drug trials, physiological investigations, natural history, and long-term effects of al trial protocols include phase i through phase iv clinical trials. The four phases are described in chapter v, "protocols using investigational new drugs and devices. When the protocol type is identified as a clinical trial, the appropriate phase of the protocol should be ng radiation use identifies the proposed use of radiation in research participants. For diagnostic radiographic procedures that would be done whether the patient is in a protocol or not, or for standard patient care in the practical management of the condition).

Where uses of radiation or radioactive materials for research do not meet the criterion of medically indicated, including procedures for diagnosis or treatment that are considered experimental) the protocol must be reviewed by the radiation safety committee. Exposing healthy clinical research volunteers to radiation must be reviewed by the committee because, by definition, such volunteers should have no medical condition that would require exposure to radiation (see chapter vi, "protocols using radiation for research"). In some cases the sponsor and holder are research contact is the individual to whom the office of clinical center communications (occc) and the patient recruitment and public liaison office (prpl) will refer people who have questions about the protocol. Medical advisory investigator (mai) must be assigned to the protocol when the pi is not a member of the junior or senior staff, or when the institute clinical director, irb, or cc director considers it warranted. The mai must be a member of the junior or senior medical staff and is responsible for assisting the pi in developing clinical aspects of the protocol and consulting with the pi on clinical matters. The mai's full name, professional designation and degree, institute and branch affiliation, and telephone number should be identified on the nih-1195 ate investigator(s) (ai) are individuals other than the pi who are involved in the protocol. A useful criterion for designating an ai might be anyone who contributes out-of-the-ordinary services to the pi or subjects of a protocol. Proper documentation of ai responsibilities requires that the nih-1195 form be initialed by all ai's; ai's from institutes other than that of the pi must have their clinical directors initial the nih-1195 form or the protocol face sheet (see "protocol face sheet") to indicate the clinical director's knowledge and approval of resource prйcis is the first section of the protocol. It describes the objectives, study population, design, and outcome parameters of the protocol in 400 words or less. The application is not considered complete without the prй protocol number is the alpha-numeric identification number assigned to the protocol by the protocol coordination service center (pcsc) after the protocol has been approved by the cc director. The first two digits represent the fiscal year in which the protocol was approved; the letter(s) represent the institute abbreviation; and the last four digits represent the next available sequential number for new protocols in that fiscal year. For example, 99-ch-0001 corresponds to the first protocol approved in fiscal year 1999 from the national institute of child health and human development. The study is tracked by the protocol number in the protrak data base, the mis, in official correspondence, and all other related data ures at the bottom of the nih-1195 form are a guide to the various required signatures and approval dates in the protocol-approval process.

Having prepared and signed the nih-1195 form, the pi forwards the form and the proposed protocol to the accountable investigator for his or her approval. An accountable investigator is defined as a tenure or tenure-track investigator who is responsible and accountable for the scientific quality and the expenditure of resources for the conduct of a protocol. Otherwise, the accountable investigator signs and forwards the nih-1195 form and proposed protocol to the branch chief or department head. The protocol then goes to pre-irb scientific review (also called internal scientific review), then to the institute clinical director, and then to the irb for review and the above individuals and review bodies approve the proposed protocol, the nih-1195 form and protocol are forwarded to the pcsc. The protocol specialist's signature, the date, and the protocol number on the nih-1195 form signify that all tasks are completed and that accrual of subjects can mes thought of as a cover memo for the protocol, a protocol face sheet (figure 2) contains virtually all the information found on the nih-1195 form. Some institutes request that their pi's include a protocol face sheet with their protocol; in this circumstance, the nih-1195 form is used as a transmitting document. For other institutes, the nih-1195 form supersedes the protocol face 2: protocol face here to download cc offers guidelines that should be followed when writing research protocols (see cc policy m97-2, subject: "guidelines for writing research protocols"). Not all elements are applicable to every protocol, but taken together, they describe a clinical research study. To avoid submitting an incomplete protocol, which may lead to delay in the irb review, the new protocol should include the elements listed below. Cis: in 400 words or less, the prйcis describes the objectives, study population, design, and outcome parameters of the of contents/outline: in complex and involved protocols, it is useful to incorporate a table of uction: the introduction describes the study's background, including human-subject or animal research, and references that are relevant to the design and conduct of the study. If an ind is to be used, animal data on the drug should be ives: the precise objectives of the protocol should be stated in a few short sentences in the form of hypotheses (see "specifying the objectives"). The protocol should be soundly designed to answer the questions posed by the design and methods: the study design and methods should accurately describe the involvement expected of human subjects, including initial evaluation and screening tests, phases, procedures, and sequence of the protocol. Describe the randomization procedure, if applicable; and address the experience of investigators if procedures are to be performed for which the investigators have not been specifically icinal experimental procedures, such as the intensity and timing of apheresis, may vary sequentially during the protocol.

Separate the standard and experimental aspects of the protocol as much as ion and exclusion criteria: men, women, and children from across the united states and around the world participate as research participants on protocols conducted at nih. The criteria by which the pi includes or excludes persons from the protocol are important because the pi may generalize only to that population of which the research participants are a reasonable sample. Also, clear inclusion and exclusion criteria will help to avoid having individuals come in for initial workups only to find that the protocol is not suitable for pi may also wish to consider including healthy individuals who volunteer to participate in protocols so investigators can gather data about normal body functions. The prpl or crvp can assist the institutes with recruitment efforts and arrange to pay volunteer research ring subjects and criteria for withdrawal of subjects from the study: the pi should identify and describe the types, frequency, and duration of tests, admissions, outpatient visits, and procedures that a research participant should expect during the protocol. If a participant develops an additional condition such as pregnancy, needs surgery, or needs to be hospitalized, the protocol may require withdrawal from a particular study, although not necessarily from others. In studies done with therapeutic intent, the protocol should clarify what the off-study criteria for "deterioration" or "inadequate control" are. The protocol should also clearly state that voluntary withdrawal from the protocol is always an option for either the research participant or the is of the study: the methods used to estimate the number of research participants required in the study, the precise outcomes to be measured and analyzed, and the statistical analysis and measurement of the results should be discussed in detail in this section of the protocol. Properly interpreted, the label "statistical considerations" covers the specific objectives, design and definition of the protocol, definition of population, number of patients to be accrued, measurement of outcome, frequency of sequential data analyses, and the final analysis of the data. Steinberg suggests that the statistical considerations in a protocol be drafted by the consultant statistician, who should be familiar with the entire research -subjects protections: a protocol without the human-subjects protections section will not be accepted for review by the t selection: this section must include (a) a rationale for selecting the research participants on the basis of their risk for the disease or condition being studied, and their gender, ethnic origin, and race; (b) strategies or procedures for recruiting participants (including advertising, if applicable); and (c) justification for exclusions. Discuss what procedures or practices will be used in the protocol to minimize these individuals' susceptibility to undue influences and unnecessary risks (e. Discomforts associated with medical procedures, such as blood drawing and bone marrow aspirations, do not need exposition here because the protocol, unlike the protocol consent document, is directed primarily to a medical audience who will know what is pi must specify what compensation any healthy clinical research volunteers will receive for their time and inconvenience and for their travel and escort needs while participating on the protocol. The irb evaluates the proposed amounts to determine if they constitute financial coercion or reasonable compensation for time and of inconvenience units assigned to procedure is totally optional and determined by the institute after considering the fiscal structure of protocol (dollars allotted) and discomfort level of the procedure. Of inconvenience units assigned to procedure is totally optional and determined by the institute after considering the fiscal structure of protocol (dollars allotted) and discomfort level of the procedure.

To this end, full and informed consent must be obtained before a participant may take part in any protocol. Assent means an agreement to receive pi should describe the protocol consent or assent procedures to be followed for the protocol, including the circumstances in which consent or assent will be sought and obtained, who will seek it, the nature of the information to be given to prospective participants, and the method of documenting the consent or protocol may require several protocol consent or assent documents: for example, one protocol consent document for healthy clinical research volunteers, one for patient subjects, one for parents, and an assent document for their children. Supplemental material or documents such as flow diagrams or workup tables may be added to the protocol as appendices. Specific calendar dates written across the abscissa can help prevent the accidental omission of a needed nces: references are sequentially numbered throughout the protocol, from the introduction, with its description of the present state of knowledge, through the measures to be used, risks and discomforts expected, and other points that are attributable to specific al center resource bility of required resources will affect how quickly a protocol is implemented, how smoothly data are collected, and the validity and reliability of those data. Resource requirements are not included in the written protocol, but should be defined early in the protocol-planning process. The cc uses "protocol maps" to help identify the resource needs of each new protocol (see appendix b). Protocol map is a comprehensive document designed to assist the pi and the cc in prospective planning, patient recruitment, clinical intervention, and data generation for the protocol. The protocol map is a tool whose accuracy and potential worth are significantly determined by the pi's participation in its design and ically, protocol maps are used for the following purposes:To prospectively identify resource requirements for implementing a protocol, including the demand placed on all cc enable preplanning so that necessary resources are available on estimate protocol costs on the basis of the identified resource requirements. Secondary benefit of protocol maps is the communication fostered between the pi and those supplying the resources and services necessary to implement and sustain the protocol. Such communication increases the likelihood that all necessary protocol components will be in place before the first patient arrives, avoiding unnecessary delays. The service and care providers who are part of the protocol-map development also become vested in the optimal conduct of the pi, cc nursing department, and the cc office of financial resources management (ofrm) share responsibility for developing the protocol map. For the protocol map to be maximally effective, its development must be started as early as for developing the protocol map are listed below:The pi contacts the pcsc staff, who will in turn identify a "map coordinator. Map coordinator, who is a specially trained member of the nursing staff, coordinates protocol map creation with the ofrm reviews and amends the protocol map to incorporate relevant administrative departments whose services are required for the protocol will be included in the protocol-map development as pi reviews the protocol map, verifies its accuracy, and signs it before it is protocol map, therefore, is a comprehensive list of resources and planned events created by group effort.

By using the protocol map, all required resources and equipment can be identified and made available for prompt protocol implementation upon irb investigators underestimate the demand for resources and services in the cc. As a result, some pi's find themselves in the unfortunate situation of having an approved protocol but lacking the resources to proceed with it. Despite enormous mri capability available, this demand for imaging services may exceed the ability of the diagnostic radiology department to provide these services unless planned for well in cy service is another area where availability of resources affects protocol implementation. Use of the protocol map can assure that such medications will be examples highlight just a few instances where the map coordinator and specific cc department representatives could collaborate with the pi to identify resources that might require special attention to assure availability. Protocol maps also help with wise use of limited resources by providing the research team with a means of managing research requirements so research participants do not miss scheduled appointments and waste the spring of 1999, the cc began to redesign and computerize the protocol-mapping process to enhance its usefulness.