Application for Human Research - Health Sciences · A2.1 Key research personnel. are persons who have direct contact with subjects or their identifiable data or specimens • Include

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Human Subjects Research Protocol

Guide for Investigators

US Army Medical Research and Materiel Command Office of Research Protections

Institutional Review Board Office Headquarters, US Army Medical Research

and Materiel Command Institutional Review Board (HQ USAMRMC IRB)

This guide provides information about the human research protections requirements and the elements to include in the research protocol. Review this guide while developing the protocol and incorporate applicable and sufficient information in the protocol for the Institutional Review Board (IRB) to evaluate and approve the research.

Denote sections of the protocol that are not applicable to your research as “NA.”

VERSION # / DATE: Version and date must be updated with every change to the protocol document.

SECTION A: RESEARCH TEAM AND LOCATIONS A1. RESEARCH TEAM – Team members include the principal investigator, associate investigators, research support personnel, research coordinators, research nurses, clinical coordinators, and study coordinators. Also include in this section individuals supporting the research, e.g., statistician, ombudsman, consultants. Add additional spaces as needed and delete the space for roles not applicable to the study. A2. ROLES AND RESPONSIBILITIES - Complete the information for each person. Add more spaces as needed to the protocol and delete the space for roles not applicable to the study. A2.1 Key research personnel are persons who have direct contact with subjects or their identifiable data or specimens

• Include degree, certifications, etc • For military members include military rank • Note that not all study roles (e.g., Associate Investigators) will have the same study responsibilities.

However, grouping individuals with the same responsibilities together is acceptable Consider building a “back up plan” into the protocol in the event that a research team member leaves the command, will be absent for a period of more than 3 weeks (15 business days) due to deployment or TDY, or is otherwise unable to fulfill study duties as outlined in this research protocol.


• Describe research responsibilities for each team member listed in section A1, (e.g., recruiting subjects, obtaining informed consent, conducting research procedures, collecting data, analyzing data, administering drugs, monitoring the research, etc.)

The IRB Office uses the roles and responsibilities for the team members to determine whether an institution is engaged in or supporting the research. The IRB Office also determines whether there are appropriate Assurances (DoD or Federalwide Assurance) and agreements (Institutional Agreements for IRB Review (IAIR), Individual Investigator Agreements (IIA), etc) in place.

KEY STUDY PERSONNEL EXAMPLES Name: Dr. X Research Role: Associate Investigator Study Responsibilities: conduct physical exams, determine inclusion/exclusion criteria, perform research procedures including the novel surgical procedure Name(s): Ms. A, Mr. B, and Mrs. C Research Role: Nurse Research Coordinators Study Responsibilities: recruit subjects, obtain consent, collect data A2.2 Others Individuals Supporting the Research A2.2.1 Research Monitor See DODI 3216.02, Encl 3, paragraph 8 for the types of duties that may be appropriate for the research monitor for this specific research protocol. Also see below Monitoring Plan, Section C, item 7 OTHER INDIVIDUALS SUPPORTING THE RESEARCH EXAMPLE: RESEARCH MONITOR Biomedical Research Monitor Name: LTC Y, MC Research Role: Research Monitor Study Responsibilities: review subject eligibility prior to research interventions and all adverse events Social-Behavioral Research Monitor Name: Ms. Z, MSW Research Role: Research Monitor Study Responsibilities: periodically review subject eligibility prior to research interventions and, observe the consent process initially and on a quarterly basis, assess all adverse events and unanticipated problems A2.2.2 Ombudsman - For certain types of research, DOD regulations require an ombudsman to monitor that the voluntary involvement or recruitment of the Service members is clearly and adequately stressed and that the information provided about the research is clear, adequate, and accurate. The ombudsman may also be the research monitor.


• An ombudsman is REQUIRED to be present during recruitment briefings when the research involves GREATER THAN MINIMAL RISK and involves the recruitment of Service members in a group setting

• An ombudsman is not required to be present during recruitment briefings when the research involves NO greater than minimal risk and involves the recruitment of Service members in a group setting. However, the IRB may determine that an ombudsman would be appropriate to monitor that the voluntary nature of the Service members’ participation in the research is clearly and adequately stressed and that the information provided about the research is clear, adequate, and accurate

• When recruitment of non-Service members occurs in a group setting, the IRB may determine that an ombudsman would be appropriate for the research

OTHER INDIVIDUALS SUPPORTING THE RESEARCH EXAMPLE: OMBUDSMAN Name: Mr. A, Administrative Assistant Research Role: Ombudsman Study Responsibilities: observe group briefings OTHER INDIVIDUALS SUPPORTING THE RESEARCH EXAMPLE: CONSULTANT Name: Thomas B, PhD Research Role: Statistician Study Responsibilities: provide consultation on modeling; data interpretation; writing technical reports A3. RESEARCH LOCATIONS - List all locations where research activities will occur. Examples: Medical Center X will serve as site where subjects will be recruited and enrolled into the study and where the study interventions will occur University X will perform data analyses X Lab will perform all coagulation evaluations for all blood samples College of X will conduct analysis of de-identified urine specimens for all performance sites X will supply the drug and matching placebo capsules, etc. A4. MULTI-SITE RESEARCH - If this institution will be the lead site and/or coordinating center for research that will be conducted at multiple institutions, provide information for the other performance sites. A lead institution is the site in charge of the core research or sponsor protocol. The lead institution manages, coordinates, and directs the institutional performances sites. The lead institution also may be a performance site, the Coordinating Center, and/or sponsor. If this research will be solely performed at your institution, mark the section as “NA.” Example: Performance Site: US Army Medical Center Performance Site Investigator: LTC B, MC IRB that will review for the Performance Site: HQ USAMRMC IRB Function/Role of Performance Site: subject recruitment, enrollment


SECTION B: RESEARCH METHODOLOGY B1. ABSTRACT Write this section in the future tense. Note the limitation of 500 words, so do NOT include the full description of the study design or procedures. This section provides the IRB a succinct overview of the research. The abstract should be a thumbnail sketch of your purpose and procedures and should be written after the rest of the protocol is written. B2. BACKGROUND AND SIGNIFICANCE This section establishes the relevance of the proposed research.

• Include a literature review that supports, in detail, the rationale for the conducting this research This review should synthesize relevant literature into a concise but complete rationale for performance of the study

• Describe any preliminary studies and findings that led to developing this research • Explain the basis for the research questions and/or research hypotheses • Clearly support the choice of research variables • Provide complete citations for all the references used in this Background section in the references

section (Section D)

B3. MILITARY RELEVANCE

• Explain how this research protocol will address military needs and/or mission requirements • If research will be conducted in theater, explain why it can only be conducted in theater and not in

CONUS B4. OBJECTIVES/SPECIFIC AIMS/RESEARCH QUESTIONS

• The objectives/aims/questions should logically proceed from the background information provided above • Ensure the objectives/aims/questions are consistent with the research design, methods, and data analysis sections

B5. RESEARCH PLAN B5.1 Research Design

• State the type of research design in one to two sentences (e.g., prospective, use of existing records/data/specimens, observational, cross-sectional, interventional, randomized, placebo-controlled, cohort, etc.). Refer to the selected definitions on the next page

• Specify the phase – Phase I, II, III, or IV – for FDA-regulated investigational drug research


Selected definitions from “Institutional Review Board Guidebook,” Chapter IV, Considerations Of Research Design (http://www.hhs.gov/ohrp/archive/irb/irb_chapter4.htm)

Case-Control Study: A study comparing persons with a given condition or disease (the cases) and persons without the condition or disease (the controls) with respect to antecedent factors.

Clinical Trial: A controlled study involving human subjects, designed to evaluate prospectively the safety and effectiveness of new drugs or devices or of behavioral interventions.

Cross-Over Design: A type of clinical trial in which each subject experiences, at different times, both the experimental and control therapy. For example, half of the subjects might be randomly assigned first to the control group and then to the experimental intervention, while the other half would have the sequence reversed.

Descriptive Study: Any study that is not truly experimental (e.g., quasi-experimental studies, correlational studies, record reviews, case histories, and observational studies).

Double-Masked Design: A study design in which neither the investigators nor the subjects know the treatment group assignments of individual subjects. Sometimes referred to as "double-blind."

Experimental Study: A true experimental study is one in which subjects are randomly assigned to groups that experience carefully controlled interventions manipulated by the experimenter according to a strict logic allowing causal inference about the effects of the interventions under investigation. (See also: Quasi-Experimental Study).

Longitudinal Study: A study designed to follow subjects forward through time. Open Design: An experimental design in which both the investigator(s) and the subjects know the

treatment group(s) to which subjects are assigned. Prospective Studies: Studies designed to observe outcomes or events that occur subsequent to the

identification of the group of subjects to be studied. Prospective studies need not involve manipulation or intervention but may be purely observational or involve only the collection of data. IRBs should note that prospective studies do not qualify for exemption because the data or specimens in prospective studies are not extant at the time the study begins.

Quasi-Experimental Study: A study that is similar to a true experimental study except that it lacks random assignment of subjects to treatment groups. (See also: Experimental Study.)

Random, Random Assignment, Randomization, Randomized Conditions, Randomized Trials: Assignment of subjects to different treatments, interventions, or conditions according to chance rather than systematically (e.g., as dictated by the standard or usual response to their condition, history, or prognosis, or according to demographic characteristics). Random assignment of subjects to conditions is an essential element of experimental research because it makes more likely the probability that differences observed between subject groups are the result of the experimental intervention.

Retrospective Studies: Research conducted by reviewing records from the past (e.g., birth and death certificates, medical records, school records, or employment records) or by obtaining information about past events elicited through interviews or surveys. Case control studies are an example of this type of research.

Single-Masked Design: Typically, a study design in which the investigator, but not the subject, knows the identity of the treatment assignment. Occasionally the subject, but not the investigator, knows the assignment. Sometimes called "single-blind design."

http://www.hhs.gov/ohrp/archive/irb/irb_chapter4.htm


B5.2 Research Subjects/Population(s) B5.2.1 Subject Population(s)

• Include pertinent demographic characteristics, INCLUDING AGE • Note the size of the population from which potential subjects/samples/data will be recruited/drawn for

this research, so that it is clear the population can support the sample size • Justify any age, race, ethnicity, or gender limitations • Include a description of the control group, if applicable • Note whether the research involves pregnant women or children as primary research subjects

The DoD requires clinical investigations/clinical trials, or other similarly named research protocols that are conducted or supported by the DOD to include all races, ethnicities, and genders (DoDI 3216.02, enclosure 3, paragraph 6a). For example, women are excluded from research on the prostate; however, a man cannot be automatically excluded from research on the breast as men can have breast cancer. The IRB will determine whether the exclusions are acceptable and refer to a higher authority if a waiver is needed.

When DOD-supported or conducted research involves a human being as an ‘experimental subject’ there are unique requirements for obtaining informed consent. The DOD defines ‘research involving a human being as an experimental subject’ as an activity for research purposes where there is an intervention or interaction with a living individual for the primary purpose of obtaining data regarding the effect of the intervention or interaction (DODI 3216.02, enclosure 3, paragraph 9, and Glossary, page 38). Research involving a human being as an experimental subject is a subset of research involving human subjects. If the research involves a human being as an experimental subject, refer to the section on informed consent for additional information to include in the protocol.

B5.2.2 Number of Subjects, Records, and/or Specimens

• State the total number of research subjects • If there will be multiple performance sites that recruit and enroll subjects, state:

o the total number of subjects at all sites; o the estimated number of subjects per performance site or explain the enrollment method

among all sites, (e.g., competitive enrollment among all sites) • If the protocol involves the use of existing data/records, the number of records may be expressed as

a range of time, for example “Records of all subjects admitted to Hospital X ICU between 1 October 2011 and 31 September 2012”

Existing data means data that exist at the time the research is proposed to an institutional official or IRB.


• Estimate the number of individuals needed to consent and screen (but not necessarily enroll) to achieve the sample size.

B5.2.3 Inclusion Criteria

• List the inclusion criteria • If the inclusion criteria differ for each research group, list them separately

B5.2.4 Exclusion Criteria

• List the exclusion criteria • Clearly describe any groups of subjects, (e.g., children, etc.) or subjects with certain characteristics

(e.g., specific diseases, certain medication use, etc.) that will be excluded • If the exclusion criteria differ for each research group, list them separately • If women of childbearing potential may be subjects, consider whether pregnancy is an exclusionary

criterion • Consider whether participation in other research protocols at the same time would exclude

participation in this research B5.3 Research Procedures - Describe, in detail, EACH research intervention or procedure that all subjects (experimental and control) will experience. Use sufficient detail so that a person uninvolved in the research can understand what the subject will experience.

• If applicable, describe the subject-to-group assignment process (e.g., randomization, block randomization, stratified randomization, age-matched controls, alternating group, or other procedures), and explain the specific actions to accomplish the group assignment (e.g., computer assignment, use of table of random number, coin flip, etc.)

• Include screening procedures and/or tests o If women of childbearing age are potential subjects, explain the methods for screening for

pregnancy o Explain whether pregnancy testing will be done at other times during the research (e.g., prior to

certain procedures or medications; every x months, etc.) • Outline the schedule for research procedures, tests, specimen collection, and follow-up in

chronological order. A visual representation (e.g., a timeline) may be helpful when the research involves multiple and different procedures/interventions and time points

o Describe any special precautions that subjects should take before, during, or after the procedures

o Outline any special precautions for personnel conducting any procedures related to the research • Outline the schedule for administering instruments, survey, questionnaires

o Describe all the research instruments o Address the reliability and validity of all instruments o Provide a copy of survey forms/questionnaires/instruments, and a copy of the author’s

permission to use instruments when they are not in the public domain or are standardized forms • Explain the time commitment per visit and in total • List equipment used in the research. Include relevant information about each (e.g., operating

manual, pictures, safety certifications etc.)


B5.4 Data Collection - The information or data collected for the research must be consistent with the research objectives or hypothesis. For example, research only describing and comparing bacterial organisms colonizing two patient populations at a medical treatment facility and correlating bacteria found in wounds with bacteria identified from skin surfaces would include date, time, and location where surveillance swabs were collected, but not necessarily sepsis or mortality data.

• Describe all the data, variables (dependent and independent), and information to be collected. Alternatively, incorporate the information into a table, for example:

• If the research involves multiple data collection time points, specify what data will be collected at each

time point • Provide a copy of all data collection forms, case report forms, etc. used to document data collection.

See below Section F (Supplemental Forms and Document List) • As applicable, include information about the Genetic Information Nondiscrimination Act (GINA) and

include information regarding any potential implications for subjects in the consent form. See http://www.genome.gov/24519851 and http://www.hhs.gov/ohrp/policy/gina.html

B5.5 Managing Data and/or Human Biological Specimens for this Research - Include the following in this section, as applicable:

• Who will have access to the data/specimens and to the link between the subjects and their data/specimens

o Explain when the linkage will be destroyed. Generally a document linking the subject to his/her study code is destroyed when all research activities are complete

o Explain where and how data/specimens will be stored during this research. Explain how and when specimens will be shipped and stored at other facilities if not stored locally

o Explain any special precautions needed to handle, safely store and/or transport specimens o Explain what security measures will be implemented for transmitting data to other investigators

outside the institution, if applicable • If and when data/specimens will be destroyed and how this is accomplished (e.g., disposal upon the

completion of research) • Whether subjects have any options about the specimens or data collected, if appropriate, (e.g.,

additional blood draws, additional tests.) (Include this information in the consent form) • If the research will use data or specimens obtained from a previous research protocol, explain the

terms of the previous consent to support and verify that those research subjects gave consent for use in this or other future research

o Provide the prior consent form and/or the Repository Standard Operating Procedure • Explain what agreements will be needed or are in place for accessing and/or sharing data with other

institutions (e.g., Data Sharing Agreement (DSA), Business Agreements (BAA), etc.)

Data Element/Variable Source Operational Specification TBI diagnosis Tricare Encounter Data-Institutional

(TED-I) ICD-9 code 310.2 ICD-9 codes 800.00 through 800.99

Injury date Joint Theater Trauma Registry Date injury occurred Demographic Information Medical record Rank, Gender, Height, Weight, Race, MOS Balance Error Score System (BESS) Medical record Score

http://www.genome.gov/24519851

http://www.hhs.gov/ohrp/policy/gina.html


B5.6 Managing Data and/or Human Biological Specimens for Future Research. Include the following, as applicable, explaining:

• How the specimens/data will be used: for general future use or specific future use, and whether and how consent will be obtained for future uses

• Any choices subjects may have about future uses of their specimens o If subjects are given a menu of options regarding specimen donation for future research, describe

the procedures that will fulfill subjects’ specific request for use of specimens o Explain whether subjects may withdraw their data/specimens from storage and explain how this will

be done o Whether subjects may be recontacted for future research and given the option to decline. If so,

explain how this will be done. (Include in the consent process/form) • Whether there will be genetic testing on the specimens. Include information about the Genetic

Information Nondiscrimination Act (GINA) in the consent process and consent form • Where and how data/specimens will be stored (including shipping procedures, storage plan, etc.)

o If specimens/data will be stored at another institution, submit a copy of the Specimen Banking policy from the institution

• Who will have access to the data/specimens, and the linkage between the specimens/data and individuals

• The length of time that data/specimens will be stored • Conditions under which data/specimens will be destroyed and how (e.g., disposal upon request) • The agreements needed or that are in place for accessing and/or sharing data with other institutions

(e.g., Data Sharing Agreement (DSA), Business Agreements (BAA), etc.) B5.7 Devices, Drugs, Dietary Supplements, Nutritional Supplements, And Biologics – the HQ USAMRMC IRB and IRB Office reviews all research protocols to ensure compliance with applicable requirements. Whether a research protocol may be subject to the Food and Drug Administration (FDA) regulations is not always straightforward. Thus sufficient information regarding any devices or drugs planned for use in the conduct of the study is needed in order for the IRB to determine whether the FDA regulations apply to the research. The FDA clearance or approval status of the device or drug is critically important information, but even cleared or approved devices or drugs used in a research study may involve additional FDA regulatory requirements. Carefully complete these sections of the protocol, as applicable. If no devices or drugs will be used, mark the sections “NA” in the protocol template. If there are ANY questions during the development of the protocol regarding applicability of FDA regulations, contact the HQ USAMRMC IRB Office. B5.7.1 Devices

NOTE: “medical device” refers to an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is…intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or is intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes."

Medical devices may include mobile medical applications, lab assays, and decision algorithms. See 21 CFR 812 and the FDA’s medical devices website for additional information and guidance: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm


5.7.1.1 FDA-approved device being used in this research according to the approved labeling - Include the following for each device:

• Complete names and description of the device • Safety information • Schedule and duration for using the device

5.7.1.2 FDA-Approved device being used in this research other-than its approved labeling - Include the following for each device:

• Complete names and description of the device • Safety information • Schedule and duration for using the device • IDE number if available from the sponsor or FDA • Sponsor name • Sponsor Device Risk Determination (Non-significant Risk Device or Significant Risk Device)

NOTE: The protocol may qualify as an exempted investigation, however the device must meet one of the criteria at 21 CFR 312.2(c) (2) or (3), specifically:

• A device, other than a transitional device, introduced into commercial distribution on or after May 28, 1976, that FDA has determined to be substantially equivalent to a device in commercial distribution immediately before May 28, 1976, and that is used or investigated in accordance with the indications in the labeling FDA reviewed under subpart E of part 807 in determining substantial equivalence [21 CFR 312.2(c)(2)]

• A diagnostic device, if the sponsor complies with applicable requirements in 809.10(c) and if the testing: o Is noninvasive o Does not require an invasive sampling procedure that presents significant risk o Does not by design or intention introduce energy into a subject AND o Is not used as a diagnostic procedure without confirmation of the diagnosis by another,

medically established diagnostic product or procedure [21 CFR 312.2(c)(3)] 5.7.2 Drugs

NOTE: “drug” refers to drugs, dietary supplements, nutritional supplements, and biologics

5.7.2.1 FDA-approved and used in accordance with the approved labeling - Include the following for each drug:

• Name of the drug • Source • Dose range, schedule, and route of administration • Include the package insert or information

5.7.2.2 FDA-approved and used in a manner not in accordance with the approved labeling - Include the following for each drug:

• Name of the drug • Source • Dose range, schedule, and route of administration


• Include the package insert or information NOTE: The protocol may qualify for an exemption from the IND requirements, however the research must meet all of the criteria at 21 CFR 312.2(b). Include in this section how this research meets each criterion:

• The investigation is not intended to be reported to FDA as a well-controlled research protocol in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug

• If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation is not intended to support a significant change in the advertising for the product

• The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product

• The investigation is conducted in compliance with the requirements for institutional review (21 CFR 50) and informed consent (21 CFR 56); and

• The investigation is conducted without promoting the drug as safe or effective, without commercially distributing the drug, etc. (21 CFR 312.7) B5.7.2.3 Any drug not approved by the FDA - Include the following for each drug:

• Complete names and composition of all drugs • IND number (include documentation from the sponsor or FDA or documentation that an IND is not

required) • Sponsor name • Investigator’s Brochure (IB) • Source of the product(s) • Dose range, schedule, and administration route of the product(s) • Detailed description of washout period, if used • Duration of research product(s) use • Concomitant medications that will be allowed during the research • Any antidotes and treatments available for potential side effects • Location where research product(s) will be stored; dispensed, and how this is documented • Plan for disposition of unused research product(s)

B5.8 Statistical Analysis 5.8.1 Sample Size Estimation

• Include statistical justification for the number of subjects • Account for attrition, withdrawals, and dropouts in the sample size, as applicable

5.8.2 Data analysis

• Outline the plan for analyzing the data and ensure the analysis plan is consistent with the research objectives and methods

• Include any sub-group analyses (e.g., gender or age group) • Specify statistical methods and variables for each analysis • Discuss how potential confounding variables will be controlled in the data analysis


SECTION C: HUMAN RESEARCH PROTECTIONS

This section focuses on human research protections, precautions, and safeguards. It is critical that sufficient information is provided so that the IRB can make determinations and document that the criteria for IRB approval are satisfied. C1. RECRUITMENT AND CONSENT C1.1 Identification and Selection of Subjects - Explain how initial contact with potential subjects will be made.

EXAMPLES: Flyers Emails Review of unit admission or census data to identify potential subjects before

obtaining permission from the subject to access their private health information Medical record review Sampling lists Health care provider reviewing his/her patient status to determine whether

the individual meets inclusion criteria, etc Pre-screening via telephone using a script; oral presentation of screening

information and data are not recorded Pre-screening with prior informed consent

Some activities used to identify and recruit potential subjects may be considered “PREPARATORY TO RESEARCH.” Federal [CFR 164.512(i)(1)(ii) and ] and DoD [DoD 6025.18-R, C7.9.1.2.45] regulations require the PI represent to the covered entity/institution the following:

The use of the protected health information (PHI) is requested solely to review the PHI as necessary to prepare a research protocol or for similar purposes preparatory to research

That no PHI will be removed from the covered entity during the review The PHI for which use or access is requested is necessary for the research

Consult your institution’s Privacy Office to determine whether the method you will use to identify and recruit individuals for this research is “preparatory to research” and how the your confirmation/attestation must be made to the covered entity.


C1.2 Recruitment Process.

• Describe how, when, where and by whom potential subjects will be approached • When recruiting potential subjects in a group setting, explain whether or not an ombudsman will be

utilized (refer back to section A 2.2, “Requirement for an Ombudsman”) • Be sensitive to the potential for undue influence and therapeutic misconception to occur during

recruitment. If there is a potential for this, explain how it will be mitigated

Undue Influence, Coercion, and Therapeutic Misconception

“Coercion” - generally associated with the use of force to gain compliance “Undue influence” - refers to situations where there is an imbalance in

the relationship between individuals where one gets the other to do something that they might not have done otherwise. This can occur when recruiting in groups in the presence of senior leadership, or situations where senior headship sends a recruitment email.

“Therapeutic misconception” - refers to situations when individuals may not understand the difference between treatments they receive as part of their medical care and interventions performed for research purposes. This can occur when health care providers identify and recruit their own patients to be research subjects.

C1.3 Eligibility - Explain how, when, and by whom eligibility will be determined.

• If there will be screening tests or procedures to determine eligibility, consider whether a separate consent process and form are needed, or whether the consent process for both screening and participating in the research can be combined

• Verify whether potential subjects may be participating in other research protocols at the same time which may exclude their participation in this research C1.4 Consent Process

• Describe when and where the initial consent process will take place • Explain how privacy and time for decision-making will be provided • Explain how you will inform past, current, and future subjects about significant new findings that

may affect subjects or their willingness to continue participating in the research (e.g., revised consent form, addendum to consent form, information sheet, etc.)

• If the research involves children, explain the process for obtaining assent, if applicable, and for obtaining parental permission

The definition of child and the age of majority vary by state law. All active duty Service members and all Reserve Component members in a Federal duty status are considered adults, however DOD regulations require the IRB to consider whether recruiting Service members under 18 years of age, students at the Academies, or trainees is appropriate for the research.


Consult with your institution’s Human Protections Administrator or with the HQ USAMRMC IRB Office, as needed.

Research Involving Experimental Subjects (Refer back to section B5.2.1) Under 10 USC 980, when individuals are considered experimental subjects, informed consent must be obtained in advance from potential subjects or, if the subject cannot provide their own consent, from the subject’s legally authorized representative. In this situation, the research must intend to benefit the individual subjects; this must be addressed in the benefit section of the protocol. If in doubt about the applicability of this law, contact the HQ USAMRMC IRB Office.

C1.4.1 Research involving subjects with cognitive impairment or who lack capacity to provide informed consent Include in this section:

• How the decision-making capacity of potential subjects will be assessed • The individual who will serve as the Legally Authorized Representative (LAR) • How you will obtain initial informed consent from the LAR • The plan for reassessing subjects’ decision-making ability over the course of the research and, if

applicable, for obtaining consent from subjects who regain ability to consent after an LAR has given initial consent o The plan to inform subjects when the initial consent was obtained from the LAR, and to obtain

consent from the subject to participate in the research or withdraw. o Whether the subject/LAR has any options to ‘take back’ the already-collected data, documents,

or specimens

Legally Authorized Representative (LAR)

The definition of a LAR varies by state law, as does the relationship of the individual to the subject (e.g., spouse, siblings, children, etc.) and whether the LAR may consent for medical care or participating in research. Consult both your state law and your institutional policies as institutions may have more stringent standards for LARs.

C1.4.2 Research involving non-English speaking subjects - Explain in this section:

• Whether the consent form and other study documents will be available in the subject’s primary language. Procedures for ensuring accurate translation should be described in detail.

• Whether someone able to discuss participation in the patient’s language will be present for the consent process, or whether a short-form will be used if the potential subject does not speak or read English.

• How communicating with non-English speaking subjects will be maintained throughout their participation in the study.


C1.4.3 Research involving a waiver of the requirement to obtain informed consent OR alteration of the elements of informed consent - The human subjects protection regulations [32 CFR 219.116(d)] permit the IRB to consider approval of a consent procedure which does not include, or which alters, some or all of the elements of informed consent, or to waive the requirements to obtain informed provided the IRB finds and documents that four criteria are addressed/appropriately justified. If a waiver or alteration of informed consent is requested, explain in this section:

• Why the research involves no more than minimal risk to subjects • Why waiving the requirement to obtain informed consent or altering the elements of informed

consent will not adversely affect subjects’ rights and welfare • Why the research could not be conducted without the waiver or alteration • Whether or not subjects will be provided with information about their inclusion in this research.

If information will be provided, explain how this will be done

A waiver of the requirement to obtain informed consent is NOT PERMITTED for

Research that involves greater than minimal risk FDA-regulated research

C1.4.4 Research involving a waiver of the requirement for investigator to obtain a signed consent form - There are two scenarios in which the requirement to obtain a signed consent form may be waived:

Scenario 1: the only record linking the subject and the research would be the consent document and the principal RISK would be potential harm resulting from a breach of confidentiality. For example, research involving collecting detailed information about illegal drug use or other criminal behavior. The regulations require that the subject be asked whether s/he wants documentation linking him or her with the research. Subjects may be linked to the research by signing a consent form or by having their name recorded in the investigator's records through some other mechanism (e.g., the investigator records their name in the research records). If this scenario applies to this research, describe the plan for ascertaining the subjects’ wishes about documentation linking to the research and how their wish will be carried out.

OR Scenario 2: the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context. For example, a study involving a blood draw, completion of questionnaires and interviews to obtain medical history would qualify for a waiver, since none of the procedures require written consent outside of the research. Note, however, that the IRB may require that subjects be provided with a written statement about the research. C1.4.5 Waivers of assent or parental permission when the research involves children – There are additional federal regulations governing when the IRB may waive assent or parental permission (45 CFR 46.408 and 21 CFR 50.55). Consult with your institution’s Human Protections Administrator or with the HQ USAMRMC IRB Office, as needed. C1.4.6 Research involving data collection for the USAMRMC Volunteer Registry Database The US Army Medical Research and Materiel Command maintains a system that stores information about subjects who have participated in greater than minimal risk research conducted within the USAMRMC or in research that uses an FDA-regulated product for which the Army Surgeon General is the sponsor.


This system was established to enable commanders to meet their “duty to warn” and to enable commanders to readily answer questions concerning an individual's participation in research. Commanders have an obligation to ensure that research volunteers are adequately informed concerning the risks involved with their participation in research and to provide research volunteers with any newly acquired information that may affect their well-being when that information becomes available. The duty to warn exists even after the individual volunteer has completed his or her participation in research. If this research is greater than minimal risk research and will be conducted within the USAMRMC or involves an Army Office of the Surgeon General (OTSG) regulated product, Volunteer Registry data sheets (60-R Forms) must be completed and submitted to the MRMC at the conclusion of the study. The protocol should describe when and how the forms will be completed and submitted to the MRMC. If there is potential for attrition and loss to follow-up, consider completing Part A and B of the form at the time of enrollment, and completing Part C when the subject’s participation in the study ends. This will ensure subjects’ contact information is documented. Consult with the HQ USAMRMC IRB Office, as needed, when writing this section of the protocol.

Just so you know…there are three ways to submit 60-R forms at the end of the research:

1. Mailed or sent by delivery service to the following address: US Army Medical Research and Materiel Command, ATTN: MCMR-RPH, 810 Schreider St, Fort Detrick, MD, 21702-5000. Mailing/shipping should be via a secured method and traceable;

2. Emailed to HQ USAMRMC using encrypted email; or

3. Emailed via the SAFE Access File Exchange website (see instructions for using this method at https://safe.amrdec.army.mil/safe2/Guide.aspx)

If the Volunteer Registry Database applies to this research, the consent form must explain that information will be collected for the Volunteer Registry Database. The following language may be used: “It is the policy of the US Army Medical Research and Materiel Command that data sheets are to be completed on all volunteers participating in research for entry into this Command’s Volunteer Registry Data Base. The information entered into this confidential data base includes your name, address, Social Security Number, study name, and dates. The intent of the data base is two-fold: first, to readily answer questions concerning an individual’s participation in research sponsored or funded by the USAMRMC; and second, to ensure that the USAMRMC can exercise its obligation to ensure research volunteers are adequately warned (duty to warn) of risks and to provide new information as it becomes available. The information will be stored at the USAMRMC for a minimum of 75 years.”

C2. COMPENSATION FOR PARTICIPATION – Provide a detailed description of your plan to compensate subjects. Include in the description:

https://safe.amrdec.army.mil/safe2/Guide.aspx


• The schedule, amount, and method of payments • The total amount subjects can receive for completing the study • The plan for pro-rating compensation should a subject withdraw prior to the completion of all study

activities, as applicable

Subjects may be liable for reporting payment earned as a research subject to IRS for income purposes (>$600/year). Although it is the individual’s responsibility, you may wish to include this information in the consent form or other information sheets that will be provided to the subject.

There are three key factors to consider when addressing compensation in the protocol:

• Are the subjects federal personnel (active duty or civilian)? • If the subjects are federal personnel, are they participating in an on-duty or off-duty status? • Are the funds used to pay subjects coming directly from a federal source?

Refer to DODI 3216.02, Enclosure (3), paragraph 11 for guidance on compensation for federal employees, and/or consult with your institution’s Human Protections Administrator or with the HQ USAMRMC IRB Office. C3. WITHDRAWAL FROM RESEARCH PARTICIPATION If there is potential that a subject could decide to withdraw from the research, explain the process for withdrawal and specify whether or not the subject may withdraw their specimens/data from the research. Also describe under what, if any, anticipated circumstances the investigator or others might stop a subject’s participation (e.g., subject not following research procedures, increased risk of harm to a subject, safety issues, loss of research funding, etc.). As appropriate to your research, explain:

• Any consequences of a subject’s decision to withdraw from the research, for example changes in medication, return of materials/equipment related to the research

• Procedures to ensure the safety of the subject and the systematic end of the subject’s participation C4. PRIVACY FOR SUBJECTS - Describe the measures to protect subjects’ privacy during recruitment, the consent process, and all research activities, etc.

Privacy generally refers to an individual’s decision or ability to share or withhold personal information from others.


C5. CONFIDENTIALITY PROCEDURES FOR RESEACH RECORDS, DATA, HUMAN BIOLOGICAL SPECIMENS

Confidential v. De-identified v. Anonymous

Confidential means that you will be able to connect the subject’s data to his or her name, but that the information will not be disclosed or shared to anyone else De-identified means the subject’s name and other identifying information is not included on the data, data collection sheets, specimens, or research records, but the subject’s identify could be determined by linking their study ID to their name, or triangulation of demographic information (for example, female, rank Navy CAPT, and Hispanic) . Anonymous means that no one, not even you or your research team will be able to connect the subjects’ data to his or her name.

Describe in detail the plan to maintain confidentiality of the research data, specimens, and records throughout the research and at its conclusion (e.g., destruction, long term storage, or banking). Explain the plan for securing the data (e.g., use of passwords, encryption, secure servers, firewalls, and other appropriate methods). Consult your institution’s Information Management (IM) or Information Technology (IT) experts for guidance, as appropriate.

• State whether research data, specimens, and records will be identifiable either directly or through a coded link; OR will be de-identified and not able to be re-identified; or anonymous (never linked to identifiable subject)

• If a link is necessary, explain why (for example, to link multiple datasets) and the length of time the list with the identifiers will be kept

o If the link will be maintained beyond the completion of the research provide justification for maintaining linked data indefinitely and describe the long term measures to be taken to protect the confidentiality

o Explain how the list with the link will be kept separate from research data • Explain any possible consequences to subjects resulting from a loss of confidentiality and how

breaches of confidentiality will be handled • If data will be shared electronically with other team members/collaborators outside the institution,

describe the method of transmission and safeguards to maintain confidentiality • Explain whether this study may collect information that State or Federal law requires to be

reported to other officials or ethically requires action, e.g., child or spouse abuse.

NOTE: Whenever possible, do not store subject identifiers on laptops, PDAs, or other portable devices. If you collect subject identifiers on portable devices, you MUST encrypt the devices. Certificate of Confidentiality. Investigators collecting particularly sensitive information may consider obtaining a Certificate of Confidentiality. See http://grants.nih.gov/grants/policy/coc/ and http://www.hhs.gov/ohrp/policy/certconf.html


C6. RISKS OF HARM AND MEASURES TO REDUCE THE RISKS OF HARM, AND BENEFITS OF PARTICIPATION C6.1 Risks of harm

• Identify all research risks of harm to which the subject will be exposed for each research procedure or intervention as a result of participation in this research.

• For each research procedure or intervention, describe all measures to minimize and/or eliminate risk of harms to subjects and research personnel

• Consider psychological, legal, social, and economic risks as well as physical risks. If the risks are unknown, this should be stated

• If applicable, identify any potential risks of harm to the research personnel • If women of childbearing potential may be subjects and there is potential harm to the fetus or

woman, consider whether pregnancy should be an exclusionary criterion • When applicable, include risks of harm to women of childbearing potential, pregnant women, and

the unborn fetus • Note whether there are any prohibitions from participating in this research and any other research

at the same time • Do not describe risks from standard care procedures; only describe risks from procedures done

for research purposes

C6.2 Incidental or unexpected findings

• Describe the plan to address incidental findings and unexpected findings about individuals from screening to the end of the subject’s participation in the research.

• In cases where the subject could possibly benefit medically or otherwise from the information, state whether or not the results of screening, research participation, research tests, etc., will be shared with subjects or their primary care provider.

• State whether the researcher is obligated or mandated to report results to appropriate military or civilian authorities and explain the potential impact on the subject C6.3 Potential Benefits - Describe any real and potential benefits of the research to the subject and any potential benefits to a specific community or society. If the individuals in the research are considered experimental subjects (see above B5.2.1), and they cannot provide their own consent, the protocol must describe the intent to directly benefit all subjects.

Remember payment/compensation is not a BENEFIT! C7. DATA AND SAFETY MONITORING - Regulations require that the protocol includes adequate measures for monitoring data collected to ensure the safety of subjects. The Principal Investigator and the research team are always responsible for monitoring the research throughout the conduct of the study but, depending on the study’s risk level, a formal monitoring plan may be required. Types of studies that may require a formal monitoring plan include FDA-regulated studies and greater than minimal risk studies. C7.1 Monitoring - Describe the plan to monitor the data collected, including:

• Who will conduct the monitoring to verify that data are collected and analyzed as specified in the research protocol.

• What will be monitored


• The frequency of monitoring for accuracy and completion, how often, and how the findings/observations will be documented

• Who will be responsible for monitoring the study files to ensure the appropriate regulatory and IRB documentation is on file and up to date C7.2 Research Monitor – DoDI 3216.02, Enclosure 3, Section 8 requires the appointment of a research monitor for research involving more than minimal risk to human subjects. There may be more than one research monitor (e.g., if different skills or experiences are necessary). Research that involves minimal risk to human subjects may also include a research monitor when appropriate. If your protocol includes a research monitor:

• Ensure the individual has expertise consonant with the nature of risk(s) identified within your research protocol

• Is independent of the team conducting the research involving human subjects • Describe the monitor’s role and with whom the monitor will communicate • Describe the duties of the research monitor ensuring the duties/responsibilities are based on

the specific risks or concerns about the research

In addition, some research may require independent data and safety monitoring, e.g., by a Data Safety Monitoring Committee (DSMC) or an Independent Data Monitoring Committee (IDMC). If an independent/outside monitoring group will be used, explain:

• Who will be responsible for ensuring data accuracy and integrity • How often interim data will be reviewed and by whom • Who will perform aggregate analysis of data and adverse events

C8. REPORTABLE EVENTS

Adverse events - In general, an adverse event (AE) is any unfavorable or unintended event, physical or psychological, associated with a research study, which causes harm or injury to a research subject as a result of the subject’s involvement in the research. Adverse events may be the result of the interventions and interactions used in the research; the collection of identifiable private information in the research; an underlying disease, disorder, or condition of the subject; and/or other circumstances unrelated to the research or any underlying disease, disorder, or condition of the subject.

C8.1 Expected adverse events An expected adverse event is an event previously known or anticipated to result from participation in the research or any underlying disease, disorder, or condition of the subject. Expected adverse events do not require immediate reporting to the IRB. Although all adverse events must be summarized at continuing review, only a subset of adverse events need to be promptly reported to the IRB. The IRB requires the prompt reporting of all unanticipated problems involving risk to subjects or others, serious adverse events, and all subject deaths related to participation in the research.


Address the following in this section of the protocol:

• Identify what the expected adverse events will be for this research • Describe the likelihood (frequency) of each expected event • Describe the severity of each expected event • Describe the reversibility of each event • Describe the short term management of the event • Describe any long-term implications

C8.2 Unexpected adverse events and unanticipated problems

“Unanticipated problems involving risks to subjects or others” are any incident, experience or outcome that meets all of the following criteria:

• Unexpected (unforeseen by the researcher or the research subject) given the research procedures and the subject population being studied; and

• Related or probably related to participation in the research, or if the event or problem probably or definitely affects the safety, rights and welfare of current participants; and

• Suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic or social harm) than was previously known or recognized

Address the following in this section of the protocol:

• How unexpected adverse events will be identified (e.g., interviewing subjects, physical exams, laboratory results, safety tests, etc.)

• Who will report adverse events and unanticipated problems • How often adverse events and unanticipated problems will be reviewed to determine if any

changes to the research protocol or consent form are needed • The scale that will be used to grade the severity of the adverse event. If appropriate, consider

“Common Terminology Criteria for Adverse Events v4.0 (CTCAE)” http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40

• The scale that will be used to attribute the relatedness of the event to the study procedures/ interventions (e.g., “possibly related”, “probably not related”, “definitely related”)

C8.3 Adverse device effects – The investigational device exemption (IDE) regulations define an unanticipated adverse device effect (UADE) as “any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death, was not previously identified in a nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects” (21 CFR 812.3(s)). C8.4 FDA-regulated research under IND and IDE - Describe the process for complying with FDA regulatory requirements for adverse event reporting and adverse device effects reporting to the sponsor. (www.fda.gov/downloads/RegulatoryInformation/.../UCM126572.pdf)

http://www.fda.gov/downloads/RegulatoryInformation/.../UCM126572.pdf


Examples of unanticipated problems:

Serious adverse events A breach of confidentiality or privacy that involves real or potential risk (e.g.,

unauthorized use of disclosure of protected health information) Data and safety monitoring reports that indicate that frequency or magnitude of

harms or benefits may be different than initially presented to the IRB A publication that shows that the risks or potential benefits or the research may

be different than initially presented to the IRB Change in FDA labeling or withdrawal from marketing of a drug, device, or

biologic used in a research protocol Incarceration of a participant in a protocol not approved to enroll prisoners Complaints from participants or others involved in the research that indicate

unexpected risks or cannot be resolved by the research team

SECTION D: REFERENCES

List complete citations of the publications used to develop the protocol and cited in the background/literature review. List the references in the order they are cited and number them consecutively.

SECTION E: ABBREVIATIONS AND ACRONYMS Include an alphabetical list of abbreviations and acronyms, for example:

AHRPO Army Human Research Protections Office CRF Case Report Form DMP Data Monitoring Plan DoD Department of Defense


SECTION F: DoD PRIVACY RULE AND PROTECTED HEALTH INFORMATION (HIPAA)

If your institution is a HIPAA covered entity, or if you will access/use/collect health information in collaboration with a covered entity, the DoD Privacy Rule and HIPAA regulations apply to your research.

WHAT IS PROTECTED HEALTH INFORMATION (PHI)?

All individually identifiable health information that relates to: • the individual’s past, present or future physical or mental health or condition • the provision of health care to the individual • the past, present, or future payment for the provision of health care to the

individual and that identifies the individual, or for which there is a reasonable basis to believe it can be used to identify the individual.

REMEMBER: The identifiers themselves are not the PHI; PHI is health information that becomes individually identifiable when it’s linked to one or more identifiers.

WHAT CAN IDENTIFY THE INDIVIDUAL? Names Addresses Dates except year Ages over 89 Phone numbers Fax numbers E-mail addresses Social security numbers Medical record numbers Account numbers Certificate/license numbers Health plan beneficiary

numbers’ Vehicle identifiers and serial

numbers, or license plate numbers

Device identifiers and serial numbers

Web Universal Resource Locators (URLs)

Internet Protocol (IP) address numbers

Biometric Identifiers, including finger and voice prints

Full face photographic images and any comparable images

Any other unique identifying number, characteristic, or codes

If your research requires the use/collection/disclosure (i.e., sharing) of PHI, complete a HIPAA Authorization template. Follow your institutional policy for using a free-standing HIPAA Authorization form or incorporating the HIPAA information into the research consent form. If your research involves a waiver or alteration of the requirement to obtain HIPAA Authorization, complete the appropriate IRB Office template.