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 PIs 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 PIs 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 panels 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 Departments
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 MPAs. The Office
of Human Subjects Research (OHSR) can provide copies of the list
of MPA-holding institutions. MPAs 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 organizations 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. PIs 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://ohrs.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 patients medical record, or may be stored
either electronically or on paper in the PIs 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 CCs 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, "Whats
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 PIs or as Medical Advisory Investigators on
protocols. The PIs 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 protocols
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 institutions 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 protocols 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 employees 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 protocols 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 Contacts
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 patients
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 MAIs. There can
be only one MAI for a protocol. The MAIs 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 AIs full
name, professional designation and degree, Institute and branch
affiliation, and telephone number should be recorded on the NIH-1195
form. Additional AIs may be listed on a separate sheet
of paper. Proper documentation of AI responsibilities requires
that the NIH-1195 form be initialed by all AIs; AIs
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 Directors knowledge and approval
of resource use.
- The Précis 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 précis
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 précis.
- 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 specialists 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 PIs 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
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."
- Précis: In 400 words or less, the précis
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 studys
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 participants 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 volunteers 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 CCs "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.
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 PIs 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 PIs 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.
|