Basic Elements of a Protocol
The following outlines the basic elements of a research protocol. The IRB templates will provide more specific requirements.
Table of Contents
Sponsor's protocols typically include a table of contents. The UVA IRB protocol templates do not require a table of contents.
The introduction should indicate the specific reasons or rationale for performing the study, the hypotheses, study design ( e.g. , record review, questionnaire, specimen collection, interview, prospective evaluation of a drug or device), and an overview of the literature on comparable studies. If applicable, Principal Investigators should briefly describe the intervention, treatment, drugs, or devices to be used.
A hypothesis is a tentative statement that proposes a possible explanation to some phenomenon or event. A useful hypothesis is a testable statement which may include a prediction. The key word is testable . That is, you will perform a test of how two variables might be related. This is when you are doing a real experiment. You are testing variables.
Objectives and Rationale
The objectives of the study should be:
- based on the research question(s);
- limited in scope and number;
- based on specific quantifiable endpoints; and
- congruent with the study design.
The scientific rationale should provide enough information to answer the question, "Why should this study be done?" It should contain a referenced review of the literature specifically pertaining to the reasons for the current study and previous investigations that lead the investigator to pose the specific question. In addition, it should include a justification of the research design and the use of any placebos.
Methods and Procedures
This section describes the study design, the study population, the research intervention, if applicable, sample selection, and an appropriate analytic plan. Specific recommendations for presenting study methods are presented below.
For Clinical Research
The Methods section for clinical study protocols evaluating a drug, device or a treatment modality should explain the treatment plan. Baseline diagnostic tests, initial laboratory assessments for determining eligibility of a potential subject to enter the trial, and any procedures, physical exams, tests, interviews, videotapes, and the amount of time the subject will be involved in the study should be detailed. Principal Investigators should consider including a table or schematic of study events by visit to clarify for the IRB reviewers what tests, procedures, etc. will be done and when they will be done.
Principal Investigators should make clear which interventions and procedures are standard clinical care for the subject's condition and which are experimental or, if not experimental, are being performed solely as a result of the subject's participation in the clinical research.
Principal Investigators should discuss (1) the procedures for monitoring the subject's condition and (2) reasons for dropping any participant from the study (e.g. , relapse, lack of subject compliance).
Subject Population Selection and Inclusion/Exclusion Criteria
Subject Selection and Inclusion Criteria
UVA recognizes its responsibility to create an environment in which the equitable selection of research participants is fostered. Therefore, Principal Investigators must provide the IRB the details on the proposed involvement of humans in the research. Principal Investigators must describe the number of subjects and observations necessary to obtain statistically valid results. The type of study design and the procedures for randomization, blinding, crossover, controls (positive and negative), and, washout, as applicable, must all be explained. Principal Investigators must specify the
- characteristics of the subject population,
- numbers of subjects ( i.e. , the number of subjects required to obtain statistically valid results),
- age ranges of subjects,
- health statuses of subjects, and
- the gender composition and racial/ethnic composition of the subject population. If ethnic, racial and gender estimates are not specified, the Principal Investigator must provide a clear rationale for exclusion of this information.
Methods for subject screening and eligibility should be described in detail. Screening for enrollment into a study entails careful evaluation of the potential subject on the basis of the criteria that are stated in the protocol.
Subject eligibility criteria should be listed, including age, sex, race/ethnicity, and other inclusion and exclusion criteria. If a potential subject conforms to those preliminary criteria, more specific screening evaluations can be performed, such as the taking of a medical history, a physical examination, and clinical laboratory tests, such as a complete blood count with differential; blood chemistry analysis ( e.g. , electrolytes, cholesterol, and triglycerides), urinalysis, an electrocardiogram, and blood pressure.
The protocol should state the limits of acceptability for the aforementioned evaluations; for example, it should define a normal range for the clinical laboratory tests and include appropriate statements about the interpretation of those tests ( e.g. statements on borderline values).
If the proposed study may include a vulnerable or special subject population, investigators shall refer to the additional requirements for these subject populations.
Subject Exclusion Criteria
Exclusion criteria may include pregnant women (unless the research is on pregnancy), severity of disease, mental incompetence, use of other medication concomitantly, or presence of other diseases. Principal Investigators must explain and justify the exclusion of women and/or minority groups and children
Women and Minorities
All research involving human subjects should be designed and conducted to include members of both genders and members of minority groups, unless a clear and compelling rationale and justification establishes that such inclusion is inappropriate with respect to the health of the subjects or the purpose of the research.
The NIH acknowledges clear scientific and public health reasons for specifically including members of minority groups in studies of health problems that disproportionately affect U.S. racial/ethnic minority populations. In attempting to include minority groups, Principal Investigators should assess the theoretical and/or scientific connections between race/ethnicity in the topic of study. FDA Guidelines require that subjects recruited to trials reflect the population that will receive the drug/therapeutic intervention when it is marketed or approved for administration. FDA Guidelines also recommend that "representatives of both genders be included in clinical trials in numbers adequate to allow detection of clinically significant gender related differences in drug response."
For NIH-defined Phase I and II clinical trials, the systematic inclusion and reporting of information on women and minorities and minority subpopulations is generally required to increase the scientific base of knowledge about them. For Phase III clinical trials, the design of the trials must reflect the current state of knowledge about any clinically important gender and/or race/ethnicity differences in the response to the intervention. Evidence may include data from prior animal studies, clinical observations, metabolic studies, genetic studies, pharmacology studies, and observational, epidemiologic and other relevant studies. The nature of the evidence should be used to determine the extent to which women, men and members of minority groups and their subpopulations must be included. In addition, national statistics on the disease, disorder or condition under study and national population statistics should be used in designing Phase III clinical trials.
Studies should employ a design with gender, racial and/or age representations appropriate to the known incidence/prevalence of the disease or condition being studied. If subjects of a certain gender, race or age group are to be excluded and it can reasonably be assumed that the drug or therapeutic intervention when approved will be administered to both sexes and all age and racial groups, the investigator must clearly explain and justify such exclusion.
It is not expected that every minority group and subpopulation will be included in each study; however, broad representation and diversity are the goals, even if multiple clinics and sites are needed to accomplish it.
Minority groups recognized by NIH include:
- American Indian or Alaskan Native (person having origins in any of the original peoples of North America , and who maintain cultural identification through tribal affiliation or community recognition);
- (ii) Asian or Pacific Islander (person having origins in any of the original peoples of the Far East, Southeast Asia, the Indian subcontinent or the Pacific Islands and Samoa);
- (iii) Black, not of Hispanic origin (a person having origins in any of the black racial groups of Africa ); and
- (iv) Hispanic (a person or Mexican, Puerto Rican, Cuban, Central or South American or other Spanish culture or origin regardless of race).
Each minority group may contain subpopulations which are delimited by geographic origins, national origins and/or cultural differences. The minority group or subpopulation to which an individual belongs is determined by self-reporting.
Subject Withdrawal Criteria
A protocol shall include subject withdrawal criteria and procedures specifying
- when and how to withdraw subjects from the trial,
- the type and timing of data to be collected for withdrawn subjects,
- whether and how subjects will be replaced, and
- the follow-up for such subjects.
If data collected for research purposes has clinical significance for individuals in the study but the data will be analyzed at another institution, resulting in substantial delay in receipt of important clinical findings affecting the subject's welfare, Principal Investigators should specify how they intend to monitor the subject locally.
Risks and Benefits
Per DHHS and FDA regulations (45 CFR 46.111 and 21 CFR 56.111) two of the required criteria for granting IRB approval of the research are:
- Risks to subjects are minimized by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.
- Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. In evaluating risks and benefits, the IRB will consider only those risks and benefits that may result from the research, as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research.
- Benefit: A valued or desired outcome; an advantage.
- Risk: The probability of harm or injury (physical, psychological, social, or economic) occurring as a result of participation in a research study. Both the probability and magnitude of possible harm may vary from minimal to significant. Federal regulations define only "minimal risk."
- Minimal Risk: A risk is minimal where the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater, in and of themselves, than those ordinarily encountered in daily lives of the general population or during the performance of routine physical or psychological examinations or tests.
- Minimal Risk for Research involving Prisoners: The definition of minimal risk for research involving prisoners differs somewhat from that given for non-institutionalized adults. Minimal risk is in this case is defined as, "the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives , or in the routine medical, dental or psychological examinations of healthy persons ."
Overview of Risks and Benefits
There are two sources of confusion in the assessment of risks and benefits. One arises from the language employed in the discussion:
- "Risk" is a word expressing probabilities;
- "Benefits" is a word expressing a fact or state of affairs.
It is more accurate to speak as if both were in the realm of probability : i.e., risks and expected or anticipated benefits.
Confusion also may arise because "risks" can refer to two quite different things:
- those chances that specific individuals are willing to undertake for some desired goal; or
- the conditions that make a situation harmful to a subject.
Researchers should provide detailed information in the IRB protocol about potential risks and benefits associated with the research, and provide information about the probability, magnitude and potential harms associated with each risk.
The IRB is responsible for evaluating the potential risks and weighing the probability of the risk occurring and the magnitude of harm that may result. It must then judge whether the anticipated benefit, either of new knowledge or of improved health for the research subjects, justifies inviting any person to undertake the risks. The IRB cannot approve research in which the risks are judged unreasonable in relation to the anticipated benefits. The IRB must:
Identify the risks associated with the research, as distinguished from the risks of therapies the subjects would receive even if not participating in research;
- Identify the risks associated with the research, as distinguished from the risks of therapies the subjects would receive even if not participating in research;
- Determine that the risks will be minimized to the extent possible [see below];
- Identify the probable benefits to be derived from the research;
- Determine that the risks are reasonable in relation to be benefits to subjects, if any, and the importance of the knowledge to be gained; and
- Assure that potential subjects will be provided with an accurate and fair description (during consent) of the risks or discomforts and the anticipated benefits.
Types of Risk to Research Subjects
The risks to which research subjects may be exposed have been classified as physical, psychological, social, and economic.
Physical Harms: Medical research often involves exposure to minor pain, discomfort, or injury from invasive medical procedures, or harm from possible side effects of drugs. All of these should be considered "risks" for purposes of IRB review. Some of the adverse effects that result from medical procedures or drugs can be permanent, but most are transient. Procedures commonly used in medical research usually result in no more than minor discomfort (e.g., temporary dizziness, the pain associated with venipuncture).
Some medical research is designed only to measure more carefully the effects of therapeutic or diagnostic procedures applied in the course of caring for an illness. Such research may not entail any significant risks beyond those presented by medically indicated interventions. On the other hand, research designed to evaluate new drugs or procedures may present more than minimal risk, and, on occasion, can cause serious or disabling injuries.
Psychological Harms: Participation in research may result in undesired changes in thought processes and emotion (e.g., episodes of depression, confusion, or hallucination resulting from drugs, feelings of stress, guilt, and loss of self-esteem). These changes may be transitory, recurrent, or permanent. Most psychological risks are minimal or transitory, but some research has the potential for causing serious psychological harm.
Stress and feelings of guilt or embarrassment may arise simply from thinking or talking about one's own behavior or attitudes on sensitive topics such as drug use, sexual preferences, selfishness, and violence. These feelings may be aroused when the subject is being interviewed or filling out a questionnaire. Stress may also be induced when the researchers manipulate the subjects' environment - as when "emergencies" or fake "assaults" are staged to observe how passersby respond. More frequently, however, is the possibility of psychological harm when behavioral research involves an element of deception.
Invasion of privacy is a risk of a somewhat different character. In the research context, it usually involves either covert observation or "participant" observation of behavior that the subjects consider private.
The IRB must make two determinations:
- is the invasion of privacy involved acceptable in light of the subjects' reasonable expectations of privacy in the situation under study; and
- is the research question of sufficient importance to justify the intrusion?
The IRB must also consider whether the research design could be modified so that the study can be conducted without invading the privacy of the subjects.
Breach of confidentiality is sometimes confused with invasion of privacy, but it is really a different risk. Invasion of privacy concerns access to a person's body or behavior without consent; confidentiality of data concerns safeguarding information that has been given voluntarily by one person to another.
Some research requires the use of a subject's hospital, school, or employment records. Access to such records for legitimate research purposes is generally acceptable, as long as the researcher protects the confidentiality of that information. However, it is important to recognize that a breach of confidentiality may result in psychological harm to individuals (in the form of embarrassment, guilt, stress, and so forth) or in social harm (see below).
Social and Economic Harms: Some invasions of privacy and breaches of confidentiality may result in embarrassment within one's business or social group, loss of employment, or criminal prosecution. Areas of particular sensitivity are information regarding alcohol or drug abuse, mental illness, illegal activities, and sexual behavior. Some social and behavioral research may yield information about individuals that could "label" or "stigmatize" the subjects. (e.g., as actual or potential delinquents or schizophrenics). Confidentiality safeguards must be strong in these instances.
Participation in research may result in additional actual costs to individuals. Any anticipated costs to research participants should be described to prospective subjects during the consent process.
Ways to Minimize Risk
- Provide complete information in the protocol regarding the experimental design and the scientific rationale underlying the proposed research, including the results of previous animal and human studies.
- Assemble a research team with sufficient expertise and experience to conduct the research.
- Ensure that the projected sample size is sufficient to yield useful results.
- Collect data from standard-of-care procedures to avoid unnecessary risk, particularly for invasive or risky procedures (e.g., spinal taps, cardiac catheterization).
- Incorporate adequate safeguards into the research design such as an appropriate data safety monitoring plan, the presence of trained personnel who can respond to emergencies, and procedures to protect the confidentiality of the data (e.g., encryption, codes, and passwords).
Provisions for Treatment of Adverse Events
Principal Investigators should conduct a detailed and appropriate literature review, and should detail:
- all possible risks to the subject, whether physical, psychological, social, economic, legal, or
- where the research may present a legal risk to subjects through a loss of confidentiality, address the need for a Certificate of Confidentiality.
If other methods of research present fewer risks, Principal Investigators should describe those, if any, that were considered and why they will not be used.
Any potential for discomfort associated with any test or procedure performed for research purposes should be noted.
In general, risks to subjects must be minimized
- by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk and
- whenever appropriate, by using data and procedures already being performed on the subjects for diagnostic or treatment purposes.
For all research involving any risk of physical injury (including any adverse effect affecting the body, such as rashes and infections) these risks must be specified. If there are none, state: "There are no risks of physical injury . " However, if there are risks of physical injury, the protocol should state the potential injury, a careful estimate of its probability and severity, and its potential duration and the likelihood of its reversibility.
There should be a statement as to whether these risks are presented by:
- a procedure or modality performed or administered as part of standard care or
- a procedure or modality performed or administered solely as a result of the subjects participation in the research protocol.
Principal Investigators should specify:
- quantities of body fluids or tissues ( e.g. , volume of blood, urine, saliva, number of biopsies),
- the time the subject will have to spend being tested, and
- the duration of the study.
Discussion of the risks should also include the risks of non-treatment.
If drugs or medical devices are being used which have known potential adverse side effects Principal Investigators should indicate if side effects are reversible.
Risks associated with a drug washout period, non-treatment or discontinuation of active drugs must be addressed by Principal Investigators.
Principal Investigators shall include a description of procedures (including confidentiality safeguards) for protecting against or minimizing injuries (physical, psychological and social) and provide an assessment of their likely effectiveness. There should be a clear statement about procedures for early detection of adverse effects and what steps, if any, will be taken to avoid injury to subjects, for example, the subject might be withdrawn from the study or a corrective drug might be administered.
The Principal Investigator should indicate where subjects will be recruited ( e.g. in patient unit, walk in clinic, emergency room, ICU, or outside of UVa). The Principal Investigator should also note whether normal controls are to be used and, if applicable, recruitment methods ( e.g. , advertisements). .
The IRB reviews the information contained in advertisements and other subject recruitment material and the mode of its communication. The IRB also reviews the format of any Internet information and the final copy of printed advertisements to evaluate the relative size of type used and other visual effects.
Review Preparatory to Research and Recruitment
IRB-HSR review and approval is required prior to initiating research involving health information. Investigators are not authorized to contact potential research subjects identified in reviews preparatory to research unless they are directly responsible for care of the potential subject and entitled to PHI as a result of that duty.
NOTE: All recruitment materials must be approved by the IRB prior to use. Information about recruitment materials, IRB-HSR submission process, and templates are available on the IRB-HSR Website under Subject Selection, Recruitment and Compensation .
It is not uncommon for subjects to be paid for their participation in research, especially in the early phases of investigational drug or device research or in behavioral and epidemiological research which require a significant time commitment on the part of the subject. The investigator should set forth the compensation plan in the protocol. Plans which call for the entire payment being made at the completion of the protocol may appear to be coercive.
Justification for not collecting the tax information.
Subjects may also be reimbursed for out of pocket expenses related to participation (travel costs, parking expenses, child care, etc.) If such monetary compensation or reimbursement is to be offered, investigators should state the amount subjects are to receive. To view additional information on the difference between compensation and reimbursement click on “More Information”. Researchers should be aware of the Compensation to Research Trial Participants Procedure from the Office of the Vice President for Research. The procedure requires the researcher to provide justification if compensation cannot be done via the UVa Oracle System or if the researcher is unable to obtain tax information such as name, address, and Social Security number of recipient of compensation. For additional info see:
Justification for use of an alternative method of compensation
Study Management and Personnel
The Principal Investigator should name the professional staff who will be performing the study as sub-investigators, the research study coordinators, and other study support staff. Study staff must complete the UVA required CITI training program. Where specimens or data will be collected and stored, the Principal Investigator should indicate who will be responsible for storage, under what circumstances data or specimens will be released, what future types of research are anticipated using the specimens or data, and what steps will be taken to protect confidentiality ( i.e. , all identifiers stripped or, if coded, persons with access to code and location of code). Methods for protecting the security of information should be included.
In long term studies, study management issues that the Principal Investigator should consider are: the continuity of study personnel; availability of co-investigators; the timing of periodic review of data to assess trends; continuing training for data managers or study personnel to eliminate deviations from the protocol; and the investigator's plan, if any, to "re consent" subjects and obtain authorization over a number of years.
If the study is a Phase I or Phase II clinical trial and provides for a Data and Safety Management Board, those provisions should be included in the Data and Safety Monitoring Plan.
Confidentiality and Data Storage
When appropriate, the subject should be assured that steps will be taken to assure confidentiality. The Principal Investigator should explain how subject confidentiality will be preserved, how data will be kept confidential and used for professional purposes, and whether data will be coded and where the data will be kept ( i.e. , in locked files). This is particularly important in studies in which information will be recorded which, in the view of the subject, is sufficiently sensitive so that he/she would not wish persons other than the investigators to have access to it. The protocol should also address any potential harm resulting. Whatever measures are taken to assure confidentiality should also be discussed in general terms in the consent form.
Certain research may qualify for additional privacy protection in the form of a Certificate of Confidentiality (federal funding is not required). Investigators may request a Certificate of Confidentiality to be issued by a Federal Agency when research is of a sensitive nature ( e.g. involves information pertaining to illegal conduct or relating to the use of alcohol or drugs, sexual attitudes, preferences or practices, mental health, or information potentially damaging to the subject's financial standing, employability or reputation) and the additional protection is judged necessary to achieve the research objectives.
Data Analysis and Evaluation Techniques
The Principal Investigator should describe the types of analyses to be performed and evaluation techniques (endpoints, pharmacodynamic assessments, outcome measurements, etc.). If the study entails the collection of specimens, the analytical procedure to be followed should be presented and referenced (unless obvious). If a new technique that has not been documented in the literature is to be used, the Principal Investigator should describe the technique or include a statement about the method that will be developed. The Principal Investigator should indicate determinations of response to therapy. These may include laboratory assays, biopsies, bone marrow testing, absence of symptoms, or normal blood levels. The definition of partial response and failure should be included.
If the study is designed to evaluate behavior through the use of subjective or objective rating scales, or to study quality of life or activities of daily living, the method of evaluation should be explained with references.
The description of the analytical and statistical techniques should be as explicit as possible. All manipulations of the data should be explained, and the statistical methods to be used should be identified. Simple statements about an "appropriate analytical technique" and an "appropriate statistical test" are discouraged; they imply that the investigator has not fully planned the study.
A reasonable list of references directly related to the study should be included.
When additional information is needed to support decisions made by the Principal Investigator, it should be included in an appendix. Typically, appendices include such information as height and weight tables, a description of analytical methodology, calculations, subject screening criteria, subjective and objective rating scales and any supportive literature. Any diagrams for new medical devices or brief reprints from journals might also prove useful.