I. GUIDELINES FOR PROTOCOL PREPARATION

This 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. It does not deal with particular problems of health and disease, but rather with some of the many customs, rules, and laws applicable to the conduct of human research at or with the Clinical Center (CC).

The CC serves a dual purpose. As a hospital, it provides care, with the goal of returning its patients to the fullest possible health and well-being. As a research hospital, however, the CC serves the broader purpose of seeking cures to human illness, disease, or disability through the most advanced clinical research program in the world.

The clinical research enterprise is admittedly complex. Because clinical research involves human research subjects, we must pay more attention to its ethical, regulatory, and procedural aspects than we do to research conducted in a laboratory setting. Moreover, the increasing complexity of the research itself also affects the process of designing and managing protocols.

Clinical Research Protocol

The 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. The CC supports approximately 950 active protocols for intramural (i.e., on-site) research. Through protocols, investigators find new and better ways to help prevent, detect, diagnose, control, and treat a wide variety of diseases.

The Principal Investigator

The Principal Investigator (PI) is the individual responsible and accountable for designing, conducting, and monitoring a protocol. The PI must be a suitably qualified member of the senior, junior, research, or adjunct staff, or a registered nurse, pharmacologist, psychologist, or other health professional. Consultants and students may not serve as PI's on protocols. The PI assumes full responsibility for the treatment and evaluation of patients, and the integrity of the research data. 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 results.

This 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 dispensing.

Investigators will find that successful clinical research involves much more than scientific considerations. A number of CC departments, such as Social Work, Spiritual Ministry, and Patient Activities, are keenly aware of the dual purpose of the CC and can greatly assist investigators if asked.

Federal Regulations

On July 12, 1974, Congress signed the National Research Act into law, creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. 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. Thus, NIH has an important obligation to provide leadership, not only in scientific discovery, but also in maintaining high ethical standards in its research activities, particularly those involving human subjects. 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 subjects.

The 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. It established three fundamental ethical principles that are relevant to all research involving human subjects: respect for persons, beneficence, and justice. "The Belmont Report" was adopted in its entirety as a statement of the Department's policy. Its ethical principles are the basis for Federal regulations, codified in title 45, Code of Federal Regulations, part 46, "Protection of Human Subjects" (45 CFR 46), and still serve as the foundation for our research behavior. 45 CFR 46 applies to research involving human subjects conducted or supported by institutions receiving DHHS funds.

The Deputy Director for Intramural Research (DDIR), on behalf of the NIH Director, is responsible for NIH compliance with 45 CFR 46. NIH has given written assurance to the Office for Human Research Protections (OHRP), formerly the Office for Protection from Research Risks (OPRR)– through its "Assurance of Compliance with DHHS Regulations for the Protection of Human Subjects" (45 CFR 46) – that it conducts and supports human-subjects research at the CC and elsewhere in compliance with these regulations. This assurance document is commonly referred to as the NIH Multiple Project Assurance (MPA). The MPA covers all human-subjects research conducted by or supported by NIH.

A number of other large research hospitals, university medical schools, and other organizations have MPA's. The Office of Human Subjects Research (OHSR) can provide copies of the list of MPA-holding institutions. MPA's must be renewed every 5 years.

When 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). An SPA is a written agreement that formally acknowledges the organization's intent to comply with DHHS regulations regarding human research subjects when conducting specific DHHS-supported research. Thus, if an NIH intramural investigator plans to collaborate in human-subjects research with an investigator at a non-MPA-holding institution, it may be necessary, depending on the nature of the collaboration, for the PI to negotiate an 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 data.

Not 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. At NIH, the Institutional Review Board (IRB) Chair is initially responsible for determining whether or not a collaboration exists on the basis of a written description of the research provided by the PI. The form "Request for SPA Negotiation" is available from OHSR. PI's and IRB Chairs who are unsure about requesting negotiation of an SPA are encouraged to contact OHSR for advice.

The DDIR and OHSR have published a brochure entitled "Guidelines for the Conduct of Research Involving Human Subjects at the National Institutes of Health," which contains information about NIH policies and procedures for conducting research involving human subjects. Copies may be requested through the OHSR. This brochure, the NIH MPA, 45 CFR 46, "The Belmont Report," and other related documents are available on the OHSR website at http://ohsr.od.nih.gov/.

Preliminary Thoughts on Writing a Protocol

Perhaps the first thing an investigator needs when developing a protocol is a testable hypothesis. Medical studies at the CC may represent simple observation over an extended period of time, yielding a great deal of knowledge, especially on the rarest of diseases. Medical studies may also represent a hypothesis based on fact, but embellished by the imagination of the investigator. For example, if the investigator knows that xyz is true of a disease, and that a form of xyz can be reduced by adding qrs in the laboratory, he or she predicts that, by administering qrs to the patient, xyz can be expected to show a reduction in the disease intensity or that xyz will change, perhaps in a laboratory test.

There are many factors – and a great deal of hard work – hidden in such a simple hypothesis: Is the literature support or personal experience sufficient to say that xyz is truly a part of the disease of interest? Is there any reason to think that what happened in the test tube could happen in the biological situation? Could and should qrs be tested in animals first? How toxic is qrs? Is it an "investigational new drug"? How will the intensity of xyz be measured? What is a reasonable estimate of the study size needed to reject the hypothesis? Will the protocol involve healthy clinical research volunteers? If so, will the experimental and healthy control groups both receive the best medication available for xyz? Can enough xyz patients be recruited, or are they already available at the CC?

The PI also needs to decide how the required information will be collected and recorded. Who will be the "observers"? Nurses, physicians, and technicians have all been used as observers, as well as the investigator. The requisite information may be written in the patient's medical record, or may be stored either electronically or on paper in the PI's records. Personal computers are available throughout the CC, which enable investigators to record their information on floppy disks. Multifunction terminals (PS/2 or Macintosh) can transfer material directly from the Medical Information System (MIS) to a floppy disk. Remember that the Privacy Act of 1974 dictates that files of records linked to specific patients be protected appropriately. The Privacy Act Coordinator of each Institute knows those requirements. The Privacy Act and other related documents are available on the U.S. Office of Personnel Management website at http://www.opm.gov/feddata/index.htm.

For 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. Will staff have the resources and contact information to track down the "no-shows"? How precise must the study calendar be? 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 protocol.

If 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. Hybrids of an inpatient hospital unit and an outpatient clinic, day hospitals allow patients to receive certain types of treatments and go home at the end of the day. Day hospitals are an innovative way for managing a large number of patients efficiently in terms of clinic space and personnel commitments. The head nurses of the day hospitals are good sources of further information.

Another 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. What happens to these subjects? Perhaps they should receive "standard treatment." For example, in a placebo-controlled trial, a person randomized to placebo may be offered the test medication after the placebo period has ended, a procedure that obviously calls for removing the mask ("blind") or disclosing to which group a patient has been assigned. One point, often not considered, is the timing for such disclosure; the preferred moment is after the last observation on the last subject. This procedure clearly carries the least risk of introducing bias; but by using it, the PI accumulates increasing numbers of patients who, finished with the trial, want to know, "What's next for me?" Mixed in with these dilemmas is the timing of when the patient is informed of the details of the study ("debriefing"), which obviously cannot precede the unmasking. Unmasking is one of the areas in the protocol design that the PI should thoroughly review with a statistical consultant.

The last part of the study preparation is writing up the clinical research process, i.e., the protocol. It may be helpful to outline a hypothetical report of the expected findings. Outlining will call attention to potential glitches and hitches in the process. The protocol must be legible and commonly is prepared on a computer, which makes it easier to track the many revisions and drafts.

This 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. Being a PI does not guarantee first-author status, and being an associate investigator does not secure coauthor status. A coauthor can describe and defend the protocol and manuscript as a whole. 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 DDIR.

Clinical Research Protocol: Initial Review Application

Form 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 bottom of the form is a guide to the various required signatures and approvals. The prospective PI prepares the form.

Figure 1: NIH-1195 -- Clinical Research Protocol: Initial Review Application

The 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. The PI must be a suitably qualified member of the senior, junior, research, or adjunct staff, or a registered nurse, pharmacologist, psychologist, or other health professional. There can be only one PI for a 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 form.
• The 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 second.
• The 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. The abbreviated title should be 30 or fewer characters and spaces.
• The Proposed Start Date and the End Date will be estimates. The start date would be the date that entering participants could begin. The end date would be the point at which no human subjects are further involved. The term "duration" may mean different things in different contexts. 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 years.

  At 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 anticipated.

• The Total Subjects to be Accrued indicates the maximum number of subjects the PI anticipates enrolling in the protocol. The number should be as precise as possible and supported by appropriate statistics (see "Determination of Sample Size"). Any adjustments to the accrual ceiling after initial approval by the IRB must be reviewed and approved by the IRB.
• Multisite Collaboration indicates whether or not the protocol entails participation from another domestic site, a foreign site, or both. Collaboration exists if the NIH intramural investigator expects something in return, such as data, authorship on a publication, samples, or even patent rights. (See "collaborate" for a more detailed discussion.) Only one box should be checked in this category. 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 applicable.
• Requested Accrual Exclusion reflects the category(ies) of people the PI requests to exclude from the study population. The PI is expected to accrue a representative cross section of the study population so that research findings can be applied to all persons at risk for the disease, disorder, or condition being studied. The PI must appropriately include women, minorities, and children in the protocol. 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 category.
• Subject Accrual Characteristics categorize the makeup of the protocol's study population to assist in future planning for resource usage.
  • Median 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 category.
  • Pediatric is the age range of child subjects to be enrolled on the protocol. More than one box may be checked in this category.
  • Impaired refers to physically and/or cognitively impaired subjects to be enrolled on the protocol. Only one box should be checked in this category.
  • Volunteer categorizes the type of volunteers to be enrolled on the protocol. Volunteer subjects fall into three categories: control or healthy clinical research volunteer; NIH employee; and NIH patient. More than one box may be checked.
    • Control 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. A small cadre of healthy clinical research volunteers is available through selected colleges, which permit their students to participate in long-term inpatient studies. Requests for student volunteers should be submitted to the CRVP.
    • NIH Employee: NIH employees may volunteer for protocols under rather strict regulations. The regulations make certain that no coercion is involved and that absence from the job is anticipated by the employee's supervisor and is not unduly extended. 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 compensation.
    • NIH Patient: An individual with a disease or disorder who is participating in a protocol studying that disease or disorder may volunteer for other studies.
  • Volunteer 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 category.
• Special 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 category.
• Keywords 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 listed.
• Protocol Types: Each protocol is assigned to one of the four intramural clinical protocol types: screening, training, natural history, and clinical trial.
  • Screening 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 monitored.
  • Training 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 monitored.
  • Natural 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 drugs.
  • Clinical 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."

  Only one protocol type should be selected that best identifies the protocol. When the protocol type is identified as a clinical trial, the appropriate phase of the protocol should be identified.

• Ionizing Radiation Use identifies the proposed use of radiation in research participants. Most protocols use radiation in a "medically indicated" fashion (e.g., 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). When the radiation exposure is described as "research indicated" (i.e., 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"). More than one box may be checked in this category.
• An Investigational New Drug (IND) is defined as a new drug or biological agent that is used in a clinical investigation. The acronym IND also refers to the "Investigational New Drug Application," to be filed with the Food and Drug Administration (FDA).

  "Test article" is the generic designation for any drug, biologic, or device that is subject to regulation under the Federal Food, Drug, and Cosmetic Act or the Public Health Service Act. Test articles may not be introduced into interstate commerce until approved by the FDA for at least one indication, unless an exemption is in effect for the article. (See chapter V, "Protocols Using Investigational New Drugs or Devices.")

  The FDA grants IND status for a test article upon the application of a "sponsor." The sponsor takes responsibility for and initiates a clinical investigation. The sponsor may be an individual, pharmaceutical company, governmental agency, academic institution, or private organization. The sponsor does not actually conduct the investigation unless the sponsor is also the investigator. An NIH individual specifically designated by a sponsor to conduct a drug study is considered, in the CC, a "holder." In some cases the sponsor and holder are identical.

• The 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. The Research Contact's full name, professional designation and degree, NIH address, telephone and fax numbers, and electronic mail address (if available) are to be recorded on the NIH-1195 form.
• Is Patient Self-Referral Allowed? The CC has a long tradition of relying on patient referrals from outside physicians. Referral by a medical practitioner familiar with the patient's care is preferable. However, in certain instances, patient self-referral may be appropriate. Regardless of the method of referral, at the time of discharge, the patient should be referred either to the referring physician or to another appropriate outside practitioner or facility for follow-up care. One box should be checked in this category.
• A 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. Consultants and students may not serve as MAI's. There can be only one MAI for a protocol. The MAI's full name, professional designation and degree, Institute and branch affiliation, and telephone number should be identified on the NIH-1195 form.
• Associate 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. If a large study will routinely involve consultation from other services (e.g., neurosurgery) and the consultation is important to the science of the study (e.g., brain biopsy), the PI should consider including the consultant as an AI. The AI's full name, professional designation and degree, Institute and branch affiliation, and telephone number should be recorded on the NIH-1195 form. Additional AI's may be listed on a separate sheet of paper. 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 use.
• The 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 prйcis could also include a brief description of anticipated risks and benefits, an estimate of the outcome, and the potential meaning for the field. The application is not considered complete without the prйcis.
• The 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 bases.
• Signatures 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. In some Institutes, that responsibility is carried by the Branch Chief or Department Head, whose signature is sufficient. 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 approval.

  Once the above individuals and review bodies approve the proposed protocol, the NIH-1195 form and protocol are forwarded to the PCSC. A protocol specialist there will obtain final approval from the CC Director. 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 begin.

Protocol Face Sheet

Sometimes 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 sheet.

Figure 2: Protocol Face Sheet

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Body of Protocol

The CC offers guidelines that should be followed when writing research protocols (see CC policy M97-2, Subject: "Guidelines for Writing Research Protocols").

Listed below are the traditional elements of a protocol. 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. Each Clinical Director may tailor the wording of the headed sections to meet the needs of his or her Institute. If some sections do not apply, state "not applicable."

• Prйcis: In 400 words or less, the prйcis describes the objectives, study population, design, and outcome parameters of the protocol.
• Table of Contents/Outline: In complex and involved protocols, it is useful to incorporate a table of contents.
• Introduction: 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. New techniques or procedures should be described and referenced. If an IND is to be used, animal data on the drug should be included.
• Objectives: 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 objectives.
• Study 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. In addition, include the alternatives to experimental therapy if they exist; give detailed procedures for treatment, dose adjustments, etc.; 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 credentialed.

  Many protocols allow changing the dose of either a therapeutic or an experimental agent. The protocol should state the conditions under which a dose change will be made, particularly in regard to failure to respond, or to toxic or untoward changes in stipulated indicators, such as the white blood cell count in cancer chemotherapy. Some services have classes or stages of reactions that permit statements such as, "The daily dose will be halved if Toxicity Grade 1 appears." An example – the Common Toxicity Criteria developed by the Clinical Therapy Evaluation Program of the National Cancer Institute (NCI) – is available electronically on the NCI website at http://ctep.info.nih.gov/CTC3/default.htm (also see appendix A).

  Nonmedicinal experimental procedures, such as the intensity and timing of apheresis, may vary sequentially during the protocol. Specify the timing of dose changes that are to be made in accord with the study plan, even in the absence of recognized variation in the measures under observation. Estimate the duration of certain within-study trials, for example, the duration of high-dose steroid therapy attempting to control the central nervous system effects of systemic lupus erythematosus. Precise criteria for such issues are difficult to provide, but the matter should be addressed in the experimental plan. Separate the standard and experimental aspects of the protocol as much as possible.

• Inclusion 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. If the criteria are too restrictive, the PI may not find enough participants. However, if the criteria are too broad, the PI may be entering persons so different that they will fail to respond to the manipulations with sufficient uniformity to enable the PI to draw conclusions.

  In March 1994, NIH issued "Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research." More information on the guidelines is available at http://www4.od.nih.gov/orwh/inclusion.html. All NIH-supported biomedical and behavioral research protocols involving human subjects must recruit women and minorities unless such inclusion is inappropriate with respect to the purpose of the research or the health of the subjects. The PI must be mindful of the need to include minorities and both genders appropriately in study populations so that research findings can be applied to all persons at risk for the disease, disorder, or condition being studied. If women or minorities are to be excluded from the research, the application or proposal must provide a clear and compelling rationale and justification to the IRB for such exclusions.

  Similarly, the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" established that children must be included in all human-subjects research conducted or supported by NIH unless scientific and ethical reasons exist for not including them. More information on these guidelines is available at http://www.nih.gov/grants/guide/notice-files/not98-024.html. This policy defines "child" as an individual under the age of 21 years. This policy and definition do not affect the human-subject-protection regulations for research on chil-dren; provisions for assent, permission, and consent remain unchanged. The policy was developed because medical treatments given to children are often based on testing done only on adults, a practice which has made scientifically evaluated treatments less available to children. Therefore, as of October 1, 1998, all proposals for research involving human subjects must include a description of plans for including children. If children are to be excluded from the research, the application or proposal must present an acceptable justification for the exclusion.

  The PI should consider the presence of other illnesses, certain past treatments, and the participant's degree of illness when identifying the criteria for subject selection. Outpatient, inpatient, and intensive-care services represent vastly different resource commitments. 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 them.

  The 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 participants.

• Monitoring 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. In addition, define stop points and criteria for withdrawing subjects ("off-study criteria") from the study or terminating the study itself. 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 PI.
• Analysis 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. Chapter IV of this manual, "Statistical Considerations for Clinical Research Studies," prepared by Seth Steinberg, Ph.D., of NCI, addresses statistical considerations in much greater detail. 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. Dr. Steinberg suggests that the statistical considerations in a protocol be drafted by the consultant statistician, who should be familiar with the entire research plan.
• Human-Subjects Protections: A protocol without the human-subjects protections section will not be accepted for review by the IRB.
• Subject 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. If subjects will be enrolled at multiple sites, describe plans for ensuring appropriate IRB review and approval at each site.

This section should also contain an explanation for involving special classes of research participants, such as fetuses, pregnant women, children, cognitively impaired individuals, prisoners or other institutionalized individuals, or others who are likely to be vulnerable. The appropriate CC policy (Medical Administrative Series) or Federal regulation subparts should be referenced when discussing the research involvement of these subjects. Discuss what procedures or practices will be used in the protocol to minimize these individuals' susceptibility to undue influences and unnecessary risks (e.g., physical or psychological) as research participants.

• Benefits and Risks/Discomforts: This section should describe the reasonably expected potential risks and benefits of the research to participants or to others.

The PI should describe the likelihood and seriousness of the potential physical, psychological, social, or legal risks. The following areas should also be addressed: the procedures, and their likely effectiveness, for protecting against or minimizing any potential risks; the protection of confidentiality; the risks of collecting, storing, and using samples or data in the future; the provisions for ensuring necessary medical or professional intervention for adverse effects of the research; and the provisions for monitoring the data col-lected to ensure the safety of participants.

The PI should also discuss why the risks to the participants are reasonable in relation to the anticipated benefits and the importance of the knowledge that may reasonably be expected to result. The description of relatively untried agents should make it clear that other toxic effects, not yet recognized, may occur and that the toxicity expectations are based on experience with animals, not humans. 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 involved.

The 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. In determining the amount of compensation a volunteer will receive, the PI should first consider the total amount of money that he or she plans on spending for each volunteer and the length of time for the procedures. The compensation rate for the volunteer's time is standardized. If any money remains after paying the volunteer for his or her time, the PI may then compensate the volunteer for travel expenses and/or assign inconvenience units to the procedure. The CC's "Inconvenience Unit Guidelines" suggest unit levels for various procedures (figure 3). Great latitude is common in applying these guidelines. The IRB evaluates the proposed amounts to determine if they constitute financial coercion or reasonable compensation for time and discomfort.

Number 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. Procedures are assigned a numerical value that is multiplied by $10. (Example: MRI may be assigned 5 inconvenience levels, or $50.)

Figure 3: Compensation for Healthy Clinical Research Volunteers

Mandatory Inpatient Outpatient (On-Site) Outpatient (Off-Site) $40 Per Diem $20 — 1st Hour or Part Thereof $10 — Each Additional Hour or Part Thereof $10 — 1st Hour or Part Thereof $5 — Each Additional Hour or Part Thereof Optional Inpatient Outpatient Escort Fee: $25 compensation for escort of patient unable to travel alone; may be paid for each admission. Escort Fee: $20 compensation for escort of patient unable to travel alone; may be paid for each visit. Inpatient/Outpatient Inconvenience Units ($10 Each) Number 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. Procedures are assigned a numerical value that is multiplied by $10. (Example: MRI may be assigned 5 inconvenience levels, or $50.)

• Protocol Consent and Assent Processes and Documents: Research at the CC is undertaken with the clear intent of making the research participant a full partner in the process. Beyond all the formal requirements, the overriding importance at the CC is teaching patients what clinical research means and how it will affect them. To this end, full and informed consent must be obtained before a participant may take part in any protocol. Children are not legally empowered to give consent; however, if they are old enough, they may have the ability to give "assent." Assent means an agreement to receive treatment.

The 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 assent.

One 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. The requirements and mechanics of the informed consent and assent process are sufficiently complex and varied to warrant a separate chapter (see chapter III, "Informed Consent and Assent").

• Appendices: Supplemental material or documents such as flow diagrams or workup tables may be added to the protocol as appendices. A properly constructed flow diagram can greatly clarify complex interactions. Workup tables typically list measures, such as laboratory work, x-ray findings, physical findings, and biopsies, along the ordinate. The abscissa represents time, in increments of days, weeks, months, or even years. A mark in the appropriate space indicates the time when the required determination will be made. Specific calendar dates written across the abscissa can help prevent the accidental omission of a needed sampling.
• References: 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 sources.

  Clinical Center Resource Use

  Availability 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).

  A 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 implementation.

  Specifically, protocol maps are used for the following purposes:

  • To prospectively identify resource requirements for implementing a protocol, including the demand placed on all CC departments.
  • To enable preplanning so that necessary resources are available on time.
  • To estimate protocol costs on the basis of the identified resource requirements.

  A 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 protocol.

  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 possible.

  Steps for developing the protocol map are listed below:

  • The PI contacts the PCSC staff, who will in turn identify a "Map Coordinator."
  • The Map Coordinator, who is a specially trained member of the nursing staff, coordinates protocol map creation with the PI.
  • The OFRM reviews and amends the protocol map to incorporate relevant administrative information.
  • CC departments whose services are required for the protocol will be included in the protocol-map development as needed.
  • The PI reviews the protocol map, verifies its accuracy, and signs it before it is implemented.

  The protocol map, therefore, is a comprehensive list of resources and planned events created by group effort. In the best of circumstances, the map is completed before the IRB review. By using the protocol map, all required resources and equipment can be identified and made available for prompt protocol implementation upon IRB approval.

  Many 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. An example of unanticipated demand for resources is the investigator who is conducting a study in which a crucial end point is change in neoplasm size. Magnetic resonance imaging (MRI) determinations of tumor mass can easily consume many hours of services. 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 advance.

  Pharmacy service is another area where availability of resources affects protocol implementation. Since the CC deals primarily with chronic, often rare, illnesses, stock medications and supplies may be different from those considered typical in another hospital. Use of the protocol map can assure that such medications will be available.

  These 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 resources.

  In the spring of 1999, the CC began to redesign and computerize the protocol-mapping process to enhance its usefulness. Improvements include:

  • Providing referring physicians and patients with concise visual information about what can be expected during the protocol.
  • Benchmarking patient progress throughout the protocol.
  • Providing a recruitment tool to enhance patient enrollment.
  • Documenting events as the patient progresses through the protocol.
  • Automatically scheduling upcoming appointments for the patient.
  • Highlighting variances from the research plan.
  • Systematically collecting research data and compiling the data into a useable format.
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