TITLE

(FULL PROTOCOL TITLE)

NIAID Protocol Number:

Sponsored by:

National Institute of Allergy and Infectious Diseases (NIAID)

Pharmaceutical Support Provided by:

Other Identifying Numbers:

IND Sponsor:

IND #

[INVESTIGATIONAL AGENT] Provided by:

Principal Investigator:

Draft or Version Number:

Day Month Year

Medical Monitor:

This template is adapted from the ICH guidance document E6 (Good Clinical Practices), Section 6.

Confidentiality Statement

This document is confidential and is to be distributed for review only to investigators, potential investigators, consultants, study staff, and applicable independent ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without written authorization from NIAID (or others, as applicable), unless it is necessary to obtain informed consent from potential study participants.

Statement of Compliance

The study will be conducted in accordance with the design and specific provisions of this IRB approved protocol, in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with Good Clinical Practice (GCP) and the applicable regulatory requirement(s). The Principal Investigator will assure that no deviation from, or changes to, the protocol will take place without prior agreement from the sponsor and documented approval from the IRB, except where necessary to eliminate an immediate hazard(s) to the trial participants. The Principal Investigator will promptly report to the IRB and the sponsor any changes in research activity and all unanticipated problems involving risk to human subjects, or others.

TITLE	1

Statement of Compliance	2

Protocol Summary	7

Précis	8

Schematic of Study Design	9

1	Key Roles	10

2	Background Information and Scientific Rationale	11

2.1	Background Information	11

2.1.1	Description of the Study Agent/Intervention(s)	11

2.1.2	Summary of Previous Pre-clinical Studies	11

2.1.3	Summary of Relevant Clinical Studies	11

2.1.4	Summary of Epidemiological Data	11

2.2	Rationale	11

2.3	Potential Risks and Benefits	11

2.3.1	Potential Risks	11

2.3.2	Potential Benefits	11

3	Study Objectives	11

3.1	Primary Objective	11

3.2	Secondary Objectives	11

3.3	Exploratory Objectives	11

4	Study Design	11

4.1	Description of the Study Design	11

4.2	Study Endpoints	11

4.2.1	Primary Endpoint	11

4.2.2	Secondary Endpoints	11

4.2.3	Exploratory Endpoints	12

4.2.4	Substudy Endpoints	12

5	Study Population	12

5.1	Participant Inclusion Criteria	12

5.2	Participant Exclusion Criteria	12

6	Study Agent/Interventions	13

6.1	Study Agent Acquisition	13

6.1.1	Formulation, Packaging, and Labeling	13

6.2	Study Agent Storage and Stability	13

6.3	Preparation, Administration, and Dosage of Study Agent/Intervention(s)	13

6.4	Study Product Accountability Procedures	14

6.5	Assessment of Participant Compliance with Study Agent/Intervention(s)	14

6.6	Concomitant Medications and Procedures	14

6.7	Precautionary and Prohibited Medications and Procedures	14

6.7.1	Prohibited Medications and Procedures	14

6.7.2	Precautionary Medications and Procedures	14

6.8	Prophylactic Medications and Procedures	14

6.9	Rescue Medications	14

7	Study Procedures/Evaluations	15

7.1	Clinical Evaluations	15

7.2	Laboratory Evaluations	15

7.2.1	Clinical and Research Laboratory Evaluations and Specimen Collection	15

7.2.2	Specimen Preparation, Handling and Shipping	15

7.2.2.1	Instructions for Specimen Storage	15

7.2.2.2	Specimen Shipment	15

7.3	Substudies	15

8	Research Use of Stored Human Samples, Specimens or Data	15

8.1	Use of Stored Samples and Data	15

8.2	Disposition of Stored Samples and Data	15

9	Study Schedule	16

9.1	Screening	16

9.2	Enrollment/Baseline	16

9.3	Active Phase	16

9.4	Follow-up	17

9.5	Final Study Visit	17

9.6	Early Termination Visit	17

9.7	Pregnancy Visit	17

9.8	Recontact of Subjects After Trial Termination	17

10	Assessment of Safety	17

10.1	Specification of Safety Parameters	17

10.2	Definition of an Adverse Event (AE)	17

10.3	Definition of a Serious Adverse Event (SAE)	18

10.4	Methods and Timing for Assessing, Recording, and Analyzing, Managing Safety Parameters	18

10.4.1	Methods and Timing for Assessment	18

10.4.1.1	AE/SAE Grading and Relationship Assignment	19

10.4.2	Recording/Documentation	20

10.4.3	Analysis/Management	20

10.5	Reporting Procedures	20

10.5.1	Specific Serious Adverse Event Requirements	21

10.6	Reporting of Pregnancy	22

10.7	Type and Duration of the Follow-up of Participants after Adverse Events	22

10.8	Modification of Study Agent(s)/Intervention(s) for a Participant	23

10.8.1	Dose / Schedule Modifications for a Participant	23

10.9	Halting Rules for the Protocol	23

10.10	Stopping Rules for an Individual Participant/Cohort	23

10.11	Premature Withdrawal of a Participant	24

10.12	Replacement of a Participant Who Discontinues Study Treatment	24

11	Clinical Monitoring Structure	24

11.1	Site Monitoring Plan	24

11.2	Safety Monitoring Plan	24

11.2.1	Safety Review Plan by the DSMB / SMC	24

12	Statistical Considerations	24

12.1	Overview and Study Objectives	24

12.2	Study Population	25

12.3	Description of the Analyses	25

12.4	Measures to Minimize Bias	25

12.5	Appropriate Methods and Timing for Analyzing Outcome Measures.	25

12.6	Study Hypotheses	25

12.7	Sample Size Consideration	25

12.8	Maintenance of Trial Treatment Randomization Codes	25

12.9	Participant Enrollment and Follow-Up	25

12.10	Planned Interim Analyses	25

12.11	Safety Review	25

12.12	Immunogenicity or Efficacy Review	25

12.13	Final Analysis Plan	25

13	Quality Control and Quality Assurance	26

14	Ethics/Protection of Human Subjects	26

14.1	The Belmont Report	26

14.2	Declaration of Helsinki	26

14.3	Institutional Review Board	26

14.4	Informed Consent Process	27

14.4.1	Assent or Informed Consent Process (in Case of a Minor)	27

14.5	Justification for Exclusion of Women, Minorities, and Children (Special Populations)	27

14.6	Participant Confidentiality	28

14.7	Study Discontinuation	28

15	Data Handling and Record Keeping	28

15.1	Data Management Responsibilities	28

15.2	Data Capture Methods	28

15.3	Types of Data	28

15.4	Source documents and Access to Source Data/Documents	28

15.5	Timing/Reports	29

15.6	Study Records Retention	29

16	Publication Policy	29

Appendix A: Scientific References	30

Appendix B: Toxicity Table	31

Appendix C: Schedule of Procedures/Evaluations	32

Appendix D: Lab Processing Flow Sheet/Template for Specimen Collection	33

Appendices: OPTIONAL	34

List of Abbreviations

ADR	Adverse Drug Reaction

AE	Adverse Event/Adverse Experience

CFR	Code of Federal Regulations

CIB	Clinical Investigator’s Brochure

CIOMS	Council for International Organizations of Medical Sciences

CLIA	Clinical Laboratory Improvement Amendment of 1988

COI	Conflict of Interest

CRADA	Cooperative Research and Development Agreement

CRF	Case Report Form

CRO	Contract Research Organization

CRIMSON	Clinical Research Information Management System of the NIAID

DCR	Division of Clinical Research

DHHS	Department of Health and Human Services

DSMB	Data and Safety Monitoring Board

DSMC	Data and Safety Monitoring Committee

FDA	Food and Drug Administration

FWA	Federal Wide Assurance

GCP	Good Clinical Practice

HIPAA	Health Insurance Portability and Accountability Act

IB	Investigator’s Brochure

ICF	Informed Consent Form

ICH	International Conference on Harmonization

IDE	Investigational Device Exemption

IEC	Independent or Institutional Ethics Committee

IND	Investigational New Drug

IRB	Institutional Review Board

ISM	Independent Safety Monitor

N	Number (typically refers to participants)

NCI	National Cancer Institute, NIH

NDA	New Drug Application

NIAID	National Institute of Allergy and Infectious Diseases

NIH	National Institutes of Health

OHRP	Office for Human Research Protections

OHSR	Office of Human Subjects Research

PHI	Protected Health Information

PI	Principal Investigator

PK	Pharmacokinetics

QA	Quality Assurance

QC	Quality Control

RCHSPB	Regulatory Compliance and Human Subjects Protection Branch

RCHSPP	Regulatory Compliance and Human Subjects Protection Program

SAE	Serious Adverse Event/Serious Adverse Experience

SMC	Safety Monitoring Committee

WHO	World Health Organization

Protocol Summary

Full Title:	Enter the full title

Short Title:	Must be 30 characters or less (count must include spaces). To check count: Select “Tools” from the menu bar; Select “Word Count”; Read “Characters (with spaces)”

Clinical Phase:	I, II, III, or IV

IND Sponsor:	Name of IND Sponsor (if applicable).

Conducted by:	Name of Network or Program

Principal Investigator:	Name of Principal Investigator

Sample Size:	N= If more than one cohort also indicate sample size per cohort.

Accrual Ceiling:	Include sample size plus an estimate for screening failures.

Study Population:	Include a brief description such as health status (e.g., healthy volunteers or HIV-positive), gender, age, etc.

Accrual Period:	Length of time to completely enroll the study. May include a projected start date.

Study Design:	Provide an overview of the study design, including description of study type (e.g., double-masked, placebo-controlled, open label, dose-finding, parallel or crossover design, randomized), study arms, sample size and schedule of interventions (e.g., vaccine administration), if applicable

Study Duration:	Start Date: End Date: Provide the total length of time participants will be on study (intervention + follow-up,) include a projected end date.

Study Agent/

Intervention Description:	Include name, dose, duration frequency, and route of administration, if applicable

Primary Objective:	Include primary outcome measures and method by which outcomes will be determined.

Secondary Objectives:	Include secondary outcome measures and method by which outcomes will be determined.

Exploratory Objectives:	(If applicable) Include exploratory outcome measure(s) that may ask separate research questions from the parent protocol.

Endpoints:	Include the primary measurements and endpoints used to determine efficacy.

Précis

Schematic of Study Design

Key Roles

For questions regarding this protocol, contact [name of appropriate NIAID staff] Branch/Division/NIAID [contact information].

Institutions:

Investigators:

Background Information and Scientific Rationale

Background Information

Description of the Study Agent/Intervention(s)

Summary of Previous Pre-clinical Studies

Summary of Relevant Clinical Studies

Summary of Epidemiological Data

Rationale

Potential Risks and Benefits

Potential Risks

Potential Benefits

Study Objectives

Primary Objective

Secondary Objectives

Exploratory Objectives

Study Design

Description of the Study Design

Study Endpoints

Primary Endpoint

Secondary Endpoints

Exploratory Endpoints

Substudy Endpoints

Study Population

Participant Inclusion Criteria

Participant Exclusion Criteria

Participation of Women:

Contraception: (if applicable) The effects of [Study Agent/Intervention] on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Females of childbearing-age, will have a pregnancy test prior to receiving [Study Agent/Intervention]. Should a woman become pregnant or suspects she is pregnant while participating in this study, she should inform study staff and her primary care physician immediately.

(Sample Language for Category C, D or X Drugs, when the drug specifies the use of two contraceptive methods)

The fetal risks associated with [Study Agent/Intervention] are not known, but pre-clinical animal data demonstrate some risk. Subjects must agree not to become pregnant or impregnate a female. Females of childbearing potential must have a pregnancy test before each dose of study agent. Because of the risk involved, subjects and their partners must use two methods of birth control. They must continue to use both methods until [XX] months after stopping study drug. Two of the birth control methods listed below may be chosen:

Hormonal contraception

Male or female condoms with or without a spermicidal

Diaphragm or cervical cap with a spermicidal

Intrauterine device (IUD)

Pregnancy: (if applicable) Pregnant women are excluded from this study because the effects of [Study Agent/Intervention] on the developing human fetus are unknown with the potential for teratogenic or abortifacient effects.

Breast-feeding: (if applicable) Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with [Study Agent/Intervention], breastfeeding should be discontinued if the mother will be treated with [Study Agent/Intervention].

Participation of Children: (if applicable) Subjects younger than 18 years of age will be excluded from the study. Because there are insufficient data regarding dosing or adverse events available in adults to judge the potential risk in children, the study is of “greater than minimal risk” and does not meet the criterion of 45 CFR 46, Subpart D, governing the participation of children in research.

Co-enrollment Guidelines: (if applicable) Co-enrollment in other trials is restricted, other than for observational studies, or those evaluating the use of a licensed medication. Study staff should be notified of co-enrollment as it may require the approval of the [investigator or medical monitor].

Study Agent/Interventions

Study Agent Acquisition

Formulation, Packaging, and Labeling

Each bottle will be individually labeled with the NIAID protocol number, dosing instructions, recommended storage conditions, the name and address of the manufacturer, randomization number, Investigational Use Statement (“Caution: New Drug – Limited by Federal [USA] Law to Investigational Use”) and that the agent should be kept out of reach of children.

Study Agent Storage and Stability

Preparation, Administration, and Dosage of Study Agent/Intervention(s)

Study Agent

Description

Dosing and Administration

Route of Administration

Dose Escalation Schedule: (if applicable)

Dose Adjustments/Modifications/Delays

Duration of Therapy

Tracking of Dose

Limitations on Prior Therapy

Use of Ancillary Medications/OTC Products/Foods

Participant Access to Study Agent at Study Closure

Control product (if applicable)

Description

Dosing and Administration

Route of Administration

Starting Dose

Dose Escalation Schedule (if applicable)

Dose Adjustments/Modifications/Delays

Duration of Therapy

Tracking of Dose

Study Product Accountability Procedures

Assessment of Participant Compliance with Study Agent/Intervention(s)

Concomitant Medications and Procedures

All concomitant prescription medications taken during study participation will be recorded [in CRIMSON or] on the case report forms (CRFs). For this protocol, a prescription medication is defined as a medication that can be prescribed only by a properly authorized/licensed clinician. Medications to be reported in the CRF are concomitant prescription medications, over-the-counter medications and non-prescription medications taken at the time of adverse events (all grades).

Precautionary and Prohibited Medications and Procedures

Prohibited Medications and Procedures

Treatment with [list specific drugs] will not be permitted unless discussed with and approved by the [study medical monitor/sponsor/investigator].

Precautionary Medications and Procedures

Prophylactic Medications and Procedures

Rescue Medications

Study Procedures/Evaluations

Clinical Evaluations

Laboratory Evaluations

Clinical and Research Laboratory Evaluations and Specimen Collection

Specimen Preparation, Handling and Shipping

Biohazard Containment

As the transmission of HIV and other blood-borne pathogens can occur through contact with contaminated needles, blood, and blood products; appropriate blood and secretion precautions will be employed by all personnel in the drawing of blood and shipping and handling of all specimens for this study, as currently recommended by the Centers for Disease Control and Prevention and the National Institutes of Health.

Instructions for Specimen Storage

Specimen Shipment

Transport of Infectious Agents

All infectious specimens will be transported using packaging mandated in the Code of Federal Regulations, 42 CFR Part 72 and according to individual carrier guidelines, as applicable.

Substudies

Research Use of Stored Human Samples, Specimens or Data

Use of Stored Samples and Data

Samples and data collected under this protocol may be used to study [XX]. [No] genetic testing will be performed. (If applicable:) Any other research or experimental treatments will be done under this or other protocols for which separate signed informed consent documents will be obtained.

Disposition of Stored Samples and Data

Access to stored samples will be limited using [either a locked room or a locked freezer]. Samples and data will be stored using codes assigned by the investigators. Data will be kept in password-protected computers. Only investigators will have access to the samples and data.

Samples and data acquired after [date] will be tracked [describe method of tracking, such as the name of the software tracking program or other logging/tracking method].

In the future, other investigators (both at NIH and outside) may wish to study these samples and/or data. In that case, IRB approval must be sought prior to any sharing of samples and/or data. Any clinical information shared about the sample would similarly require prior IRB approval.

Any loss or unanticipated destruction of samples or data (for example, due to freezer malfunction) that meets the NIH Intramural Protocol Violation definition or results in a violation that compromises the scientific integrity of the data collected for the study; will be reported to the NIAID IRB.

At the completion of the protocol (termination), samples and data will either be destroyed, or after IRB approval, transferred to another existing protocol. [describe the disposition of the specimens, the protocol will remain open, they will be sent to a repository, etc… as applicable]

Additionally, subjects may decide at any point not to have their samples stored. In this case, the principal investigator will destroy all known remaining samples and report what was done to both the subject and to the IRB. This decision will not affect the subject’s participation in this protocol or any other protocols at NIH. (If applicable)

Study Schedule

Screening

The purpose of the screening visit is to determine volunteer eligibility for study participation. Subjects, who are diagnosed with a medical condition during the screening process, (e.g., test positive for hepatitis B, hepatitis C, HIV) will be notified and referred for medical care. The following screening evaluation must be completed in the [XX] days prior to enrollment.

Enrollment/Baseline

Day 0 is defined as the day of enrollment and first administration of the study agent/intervention. Study participants must sign study participation consent form to be considered enrolled into the trial and must be randomized to a schedule [if applicable] and have all study screening complete before the first study agent/intervention is administered. Evaluations prior to the first administration are the baseline for subsequent safety evaluations. Females of reproductive potential must have a negative serum pregnancy test on Day 0 prior to enrollment and on each day of administration of the study agent/intervention.

Active Phase

(Sample Language from Vaccine Trials)

Subjects will receive [study agent] at X, X and X months. The visit and injection schedule is shown in table format in Appendix C. The protocol allows a window of ±X days in scheduling study injection visits as long as there are at least X days between injections. The injection site will alternate either the right or left deltoid muscle as the site for the primary immunization schedule. Following injections, subjects will be observed for a minimum of 60 minutes. Vital signs will be taken at 30 minutes (± 5 minutes) and 60 minutes (± 5 minutes) post-injection. If erythema or induration is present, its perpendicular diameters will be measured and recorded at each time point to determine any changes. After an intramuscular injection of [study agent] the subject will be contacted by phone at X days after injection and will have a clinic visit at that time only if indicated by adverse events. Otherwise the subject will have a follow-up visit on the ±X day following injection for clinical laboratory tests (i.e., urinalysis, CBC, differential, platelets, creatinine, ALT, PT/PTT) and photograph of the injection site.

Follow-up

Final Study Visit

Early Termination Visit

Pregnancy Visit

Recontact of Subjects After Trial Termination

Assessment of Safety

Specification of Safety Parameters

Definition of an Adverse Event (AE)

Provide a definition, specific to this protocol, of the expected vs. unexpected AEs, based on the risk profile of the Study Agent(s)/Intervention(s)( refer to the IB or package insert) and/or disease process.

Note that adverse events should be tracked starting with the initial consent through the end of study follow-up.

(Sample Language)

An adverse event (AE) is any unanticipated or unintended medical occurrence or worsening of a sign or symptom (including an abnormal laboratory finding) or disease in a study participant, which does not necessarily have a causal relationship with the study condition, procedures or study agent(s), that occurs after the informed consent is obtained.

Pre-existing conditions or illnesses which are expected to exacerbate or worsen are not considered adverse events and will be accounted for in the subject’s medical history

(Sample Language for Vaccine Studies and Some Therapeutic Trials)

Reactogenicity: Reactogenicity events are adverse events that are common and known to occur for the Study Agent(s)/Intervention(s) being studied and should be collected in a standard, systematic format using a graded scale based on functional assessment or magnitude of reaction.

Definition of a Serious Adverse Event (SAE)

Serious Adverse Event (SAE): A Serious Adverse Event is defined as an AE meeting one of the following outcomes:

Death during the period of protocol defined surveillance

Life Threatening Event (defined as a participant at immediate risk of death at the time of the event)

Inpatient hospitalization or prolongation of existing hospitalization during the period of protocol defined surveillance

Results in congenital anomaly or birth defect

Results in a persistent or significant disability/incapacity

Any other important medical event that may not result in one of the above outcomes, may be considered a serious adverse experience when, based upon appropriate medical judgment, the event may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed above. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.

(Additional sample language, applicable for an IDE protocol)

An unanticipated adverse device effect (UADE) means 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 nature, severity, or degree of incidence, or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.

Methods and Timing for Assessing, Recording, and Analyzing, Managing Safety Parameters

Methods and Timing for Assessment

AE/SAE Grading and Relationship Assignment

Intensity (severity) Scale

Each adverse event will be graded according to the Table for Grading Severity of Adverse Events (see Appendix B). All other laboratory and clinical AEs that occur in a subject, will be assessed for severity and classified into one the categories below:

Grade 1 (Mild): event requires minimal or no treatment and do not interfere with the patient’s daily activities.

Grade 2 (Moderate): event results in a low level of inconvenience or concern with the therapeutic measures. Moderate events may cause some interference with functioning.

Grade 3 (Severe): event interrupts a patient’s usual daily activity and may require systemic drug therapy or other treatment. Severe events are usually incapacitating.

Grade 4 (Life threatening): Any adverse drug experience that places the patient or participant, in the view of the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that had it occurred in a more severe form, might have caused death.

Grade 5 (Death)

Relationship Assessment

For all collected AEs, the clinician who examines and evaluates the subject will determine the adverse event’s causality based on temporal relationship and his/her clinical judgment. The degree of certainty about causality will be graded using the categories below:

Definitely Related: There is clear evidence to suggest a causal relationship, and other possible contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, occurs in a plausible time relationship to drug administration and cannot be explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be clinically plausible. The event must be pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary.

Probably Related: There is evidence to suggest a causal relationship, and the influence of other factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable time sequence to administration of the drug, is unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition.

Possibly Related: There is some evidence to suggest a causal relationship (e.g., the event occurred within a reasonable time after administration of the trial medication). However, the influence of other factors may have contributed to the event (e.g., the subject’s clinical condition, other concomitant events). Although an adverse drug event may rate only as “possibly related” soon after discovery, it can be flagged as requiring more information and later be upgraded to “probably related” or “definitely related”, as appropriate.

Unlikely: A clinical event, including an abnormal laboratory test result, whose temporal relationship to drug administration makes a causal relationship improbable (e.g., the event did not occur within a reasonable time after administration of the trial medication) and in which other drugs or chemicals or underlying disease provides plausible explanations (e.g., the subject’s clinical condition, other concomitant treatments).

Unrelated: The AE is completely independent of study drug administration, and/or evidence exists that the event is definitely related to another etiology. There must be an alternative, definitive etiology documented by the clinician.

Expected Events Related to Disease Process: Expectedness refers to the awareness of adverse events previously observed, not on the basis of what might be anticipated from the pharmacological properties of the study agent.

Recording/Documentation

At each contact with the subject, information regarding adverse events will be elicited by appropriate questioning and examinations and will be immediately recorded on a source document. Source documents will include: progress notes, laboratory reports, consult notes, phone call summaries, survey tools and data collection tools. Source documents will be reviewed in a timely manner by the research team. All reportable adverse events that are identified will be recorded on an appropriate case report form (CRF). The start date, the stop date, the severity of each reportable event, and the PI’s judgment of the AEs relationship to the study agent/intervention will also be recorded on the CRF.

Analysis/Management

Reporting Procedures

Adverse event reporting requirements to the NIAID Institutional Review Board (IRB) for this protocol are as follows:

Investigators will submit a completed serious adverse event report to the NIAID IRB within 7 days after becoming aware of a subject death, a potentially life-threatening (grade 4) serious adverse event that is possibly, probably or definitely related to investigational agent, an urgent inpatient hospitalization or transfer to the ICU.

Investigators will submit a completed serious adverse event report to the NIAID IRB within 15 days after becoming aware of any Grade 3 (severe) adverse event that is possibly, probably or definitely related to investigational agent, or an inpatient hospitalization (other than elective), a persistent or significant disability/incapacity, or a congenital anomaly/birth defect.

Investigators will report within 15 days on any other event or condition regardless of grade, which in their judgment represents an event reportable to the IRB.

Investigators will forward all IND safety reports and related FDA communications to the IRB within 15 days of receipt.

A summary of all adverse events will be reported to the NIAID IRB with a continuing review submission.

(Additional sample language for protocols involving an IDE)

Investigators will submit a report of any unanticipated adverse device effect (UADE) occurring during an investigation as soon as possible but no later than 10 working days after investigator awareness.

Specific Serious Adverse Event Requirements

(If the IND is held by RCHSPB, otherwise enter the Sponsor information including the address)

The Regulatory Compliance and Human Subjects Protection Branch (RCHSPB), National Institute of Allergy and Infectious Diseases (NIAID), of the National Institutes of Health (NIH) is the sponsor for the Investigational New Drug application (IND) filed at the U.S. Food and Drug Administration (FDA). In the interest of subject safety in RCHSPB studies and to fulfill regulatory requirements, all deaths and life-threatening SAEs due to any cause, which occur during the course of the study must be reported to the Regulatory Compliance and Human Subjects Protection Program (RCHSPP) Clinical Safety Office within 1 business day after the clinical site becomes aware of the event, and all other SAEs must be reported as soon as possible, but no later than 3 business days.

Serious adverse events will be reported to:

Regulatory Compliance & Human Subjects Protection Program (RCHSPP)
Clinical Safety Office

Phone: 301-846-5301

Fax: 301-846-6224

E-mail: rchspsafety@mail.nih.gov

In accordance with the FDA Code of Federal Regulations (CFR), the IND sponsor RCHSPB must report SAEs that are serious, unexpected, and related to the study intervention to the FDA in the form of a written IND Safety Report. Deaths and life-threatening events with any possible relationship to a study intervention must be reported to the FDA by telephone or fax as soon as possible but within 7 calendar days of RCHSPB’s awareness. This initial report must be followed by as complete a written report as possible within 8 additional calendar days. All other IND Safety Reports must be submitted to the FDA as soon as possible, but no later than 15 calendar days after RCHSPB is notified of the SAE.

SAEs that do not meet the requirements for expedited reporting and all documented adverse events will be reported to the FDA in the IND annual report.

The FDA also requires sponsors to submit a written Safety Report of all serious and unexpected adverse events to all participating investigators of a trial. All participating investigators, at all sites, will be notified of any unexpected SAEs, occurring at other sites, in an IND Safety Report from RCHSPB. RCHSPB will also notify investigators of any revisions to the protocol or to the consent, or study closure. The study investigators in this study have the responsibility of promptly reporting all SAEs so that RCHSPB can comply with these regulations.

Reporting of Pregnancy

Type and Duration of the Follow-up of Participants after Adverse Events

Monitoring of Subjects

At each contact with the subject, the investigator must seek information on adverse events by specific questioning and, as appropriate, by examination.

AEs may be observed by the Investigator and/or study staff, elicited from the subject and/or family member, reported on subject diary cards [if applicable], or volunteered by the study subject. Adverse events that had previously been reported by study subject will also be reassessed for duration, intensity and possible reoccurrence. Assessment of safety will include clinical observation and monitoring of hematological, chemical, and immunologic parameters [modify as appropriate].

Any AE that occurs between the times a study participant signs the informed consent form and the time s/he departs the study at the end of the final follow-up visit (or at the time of early discontinuation of the subject from the study for any reason) will be captured and recorded.

Follow-up of participants after Adverse Events

All SAEs and non-serious AEs reported in this study will be followed until resolution or until the investigator and the clinical/medical monitor are in agreement that the AE/SAE has stabilized and no more follow-up is required. This requirement indicates that follow-up may be required for some events after the patient discontinues participation from the study. These events will be reported to the FDA annually.

(Additional Sample Language as appropriate)

Primary care of the patient’s initial medical condition will continue to be under the auspices of their local medical provider. A letter describing the study will be sent to the subject’s primary care physician. The local medical provider will be instructed verbally and with written guidelines to contact the NIH investigators immediately for any adverse event. A toll-free number will be available to provide 24-hour access to the Principal Investigator or designee. The patient’s primary care provider(s) will be encouraged to call the PI should any change in condition be noted as compared to the subject’s baseline status. Should the occasion arise, subjects may also be treated at the NIH Clinical Center.

Modification of Study Agent(s)/Intervention(s) for a Participant

Dose / Schedule Modifications for a Participant

Halting Rules for the Protocol

The Principal Investigator will closely monitor and analyze study data as it becomes available and will make determinations regarding the presence and grading of adverse events. Evaluation of adverse events will be analyzed separately for [study agent] and [active control] and with regard to the known complications associated with [active control] administration. The study will be halted (no new enrollments and no further [administration of agent/vaccinations]) by the investigators and a report will be submitted to the IRB.

(Include the following language, with appropriate modifications)

The IRB, the NIAID, the pharmaceutical supporter(s), the FDA, or other government agencies, as part of their duties to ensure that research subjects are protected; may discontinue the study at any time. Subsequent review of serious, unexpected and related adverse events by the Medical Monitor, DSMB, ethics review committee or IRB, the sponsor(s), the FDA, and other regulatory authorities may also result in suspension of further trial interventions/administration of study agent at a site. The FDA, other regulatory authorities, and the study sponsor(s) retain the authority to suspend additional enrollment and Study Agent(s)/Intervention(s) administration for the entire study as applicable

Stopping Rules for an Individual Participant/Cohort

A study participant will be discontinued from further Study Agent(s)/Intervention(s) administration for:

Any clinical adverse event, laboratory abnormality, intercurrent illness, other medical condition or situation occurs such that continued participation in the study would not be in the best interest of the participant.

•	Development of any exclusion criteria may be cause for discontinuation.

Premature Withdrawal of a Participant

Replacement of a Participant Who Discontinues Study Treatment

Clinical Monitoring Structure

Site Monitoring Plan

Safety Monitoring Plan

Safety Review Plan by the DSMB / SMC

(Sample Language, if NIAID DSMB Monitored protocol)

The NIAID Intramural DSMB will review the IRB approved protocol, informed consent documents, the data and safety monitoring plan and any stopping guidelines prior to study initiation, unless otherwise waived by the NIAID Clinical Director. During the course of the study, the DSMB will review cumulative study data twice per year [Edit as appropriate per protocol- e.g., before dose escalation as well as twice per year] to evaluate safety, efficacy, study conduct, and scientific validity and integrity of the trial. As part of this responsibility, DSMB members must be satisfied that the timeliness, completeness, and accuracy of the data submitted to them for review are sufficient for evaluation of the safety and welfare of study subjects. The DSMB may also convene as needed if stopping criteria are met or other safety issues arise that the Principal Investigator and/or NIAID Clinical Director or designee would like the DSMB to address.

The protocol-specific statistician or other appropriate individual will provide the DSMB Executive Secretary with up to date blinding codes in a sealed envelope in the event that the DSMB will require this information to make its recommendations. The Principal Investigator will notify the DSMB of all cases of unblinding, intentional or unintentional, so that the DSMB can assess the potential impact of the unblinding on the overall integrity of the study. [Delete paragraph if study is not blinded]

The Principal Investigator will submit the written DSMB recommendations to the IRB upon receipt.

Statistical Considerations

Overview and Study Objectives

Study Population

Description of the Analyses

Measures to Minimize Bias

Appropriate Methods and Timing for Analyzing Outcome Measures.

Study Hypotheses

Sample Size Consideration

Maintenance of Trial Treatment Randomization Codes

The randomization sequence will be obtained by computer-generated random numbers and provided to the pharmacist by the statistician. The subject, the clinical staff, and the Principal Investigator will be blinded to treatment allocation. The pharmacist with primary responsibility for drug dispensing will keep the randomization code.

Participant Enrollment and Follow-Up

Planned Interim Analyses

Safety Review

Immunogenicity or Efficacy Review

Final Analysis Plan

General Design:

Study Endpoints:

Primary:

Definition:

Validity and Reliability:

Secondary:

Definition:

Validity and Reliability:

Description of the Statistical Methods to Be Employed:

Level of Significance to be Used:

Accrual and Sample Size Considerations:

Relationship(s) of Endpoints to Calculations:

Analysis Plan:.

Analysis of Variables:

Baseline Comparability:

Safety Analysis:

Efficacy Analysis:

Subpopulation Analyses of Intervention Effect:

Exploratory Analyses:

Handling of Missing and Spurious Data:

Quality Control and Quality Assurance

Following written standard operating procedures, the monitors will verify that the clinical trial is conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirements.

The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities.

Quality control procedures will be implemented beginning with the data entry system and data quality control checks that will be run on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for clarification/resolution.

Ethics/Protection of Human Subjects

The Belmont Report

In accordance with the FWA00005897: “This institution assures that all of its activities related to human subject research, regardless of funding source, will be guided by the ethical principles of The Belmont Report.” Additionally, the investigator assures that all activities of this protocol; will be guided by the ethical principles of The Belmont Report, 45 CFR 46 and all of its subparts (A, B, C and D).

Declaration of Helsinki

The investigator will ensure that this study is conducted in full conformity with the current revision of the Declaration of Helsinki, or with the International Conference for Harmonization Good Clinical Practice (ICH-GCP) regulations and guidelines, whichever affords the greater protection to the subject.

Institutional Review Board

A copy of the protocol, informed consent forms, other information to be completed by participants, such as survey instruments or questionnaires, and any proposed advertising/ recruitment materials will be submitted to the IRB for written approval.

The investigator must submit and obtain approval from the IRB for all subsequent amendments to the protocol, informed consent documents and other study documentation referenced above. The investigator will be responsible for obtaining IRB approval of the annual Continuing Review throughout the duration of the study.

The investigator will notify the IRB of violations from the protocol and serious adverse events.

Informed Consent Process

Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study and continuing throughout the individual’s study participation. Extensive discussion of risks and possible benefits of this therapy will be provided to the participants and their families. Consent forms describing in detail the study agent/intervention(s) study procedures and risks will be given to the participant and written documentation of informed consent is required prior to starting study agent/intervention. Consent forms will be IRB approved and the participant will be asked to read and review the document. Upon reviewing the document, the investigator will explain the research study to the participant and answer any questions that may arise. The participants will sign the informed consent document prior to any procedures being done specifically for the study. The participants should have sufficient opportunity to discuss the study and process the information in the consent process prior to agreeing to participate. The participants may withdraw consent at any time throughout the course of the trial. A copy of the informed consent document will be given to the participants for their records. The rights and welfare of the participants will be protected by emphasizing to them that the quality of their medical care will not be adversely affected if they decline to participate in this study.

The acquisition of informed consent will be documented in the participant’s medical records, as required by 21 CFR 312.62. The informed consent form will be signed and personally dated by the participant and the person who conducted the informed consent discussion. The original signed informed consent form will be retained in the medical chart and a copy will be provided to the participant.

Assent or Informed Consent Process (in Case of a Minor)

Justification for Exclusion of Women, Minorities, and Children (Special Populations)

Exclusion of Women: (if applicable)

Exclusion of Minorities: (if applicable)

Exclusion of Children: (if applicable)

Participant Confidentiality

The investigator will ensure that the subject’s anonymity is maintained. Subjects will not be identified in any publicly released reports of this study. All records will be kept confidential to the extent provided by federal, state and local law. The study monitors and other authorized representatives of the Sponsor may inspect all documents and records required to be maintained by the Investigator, including but not limited to, medical records. The investigator will inform the subjects that the above-named representatives will review their study-related records without violating the confidentiality of the subjects. All laboratory specimens, evaluation forms, reports, and other records that leave the site will be identified only by a coded number in order to maintain subject confidentiality. All records will be kept locked and all computer entry and networking programs will be done with coded numbers only. Clinical information will not be released without written permission of the subject, except as necessary for monitoring by IRB, [the FDA], the NIAID, the OHRP, [the pharmaceutical supporter(s)], or the sponsor’s designee.

Study Discontinuation

Data Handling and Record Keeping

Data Management Responsibilities

Data Capture Methods

Types of Data

Source documents and Access to Source Data/Documents

Study data will be collected on case report forms (CRF) designed for the study[, or an electronic data system (CRIMSON)]. The Principal Investigator is responsible for assuring that the data collected is complete, accurate, and recorded in a timely manner. Source documentation (the point of initial recording of a piece of data) should support the data collected on the case report form [or CRIMSON, and in the case of CRFs be signed and dated by the person recording and/or reviewing the data.] Source documents include all recordings of observations or notations of clinical activities and all reports and records necessary for the evaluation and reconstruction of the clinical trial. Data for CRFs will be collected during patient visits, phone calls with subjects and health care providers, patient diaries and abstracted from the medical record. The CRF form may act as the source document for the following study procedures: [Specific procedures]. It is not acceptable for the CRF to be the only record of a patient’s participation in the study. This is to ensure that anyone who would access the patient medical record has adequate knowledge that the patient is participating in a clinical trial.

Timing/Reports

Study Records Retention

Publication Policy

Following completion of the study, the investigator may publish the results of this research in a scientific journal. The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a trials-registration policy as a condition for publication. This policy requires that all clinical trials be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the National Library of Medicine. Other biomedical journals are considering adopting similar policies. It is the responsibility of the NIAID Division or Branch to register this trial in an acceptable registry. Any clinical trial starting enrollment after 01 July 2005 must be registered either on or before the onset of patient enrollment.

The ICMJE defines a clinical trial as any research project that prospectively assigns human participants to intervention or comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome. Studies designed for other purposes, such as to study pharmacokinetics or major toxicity (e.g., Phase 1 trials), would be exempt from this policy.

Appendix A: Scientific References

Appendix B: Toxicity Table

Appendix C: Schedule of Procedures/Evaluations

Evaluation	Screening

(-30 days)	Baseline

(-14 days)	Day 0	4	8	12	16	20	24	32	40	48	Prem. Disc. Evals.
Medical/Medication History
Clinical Assessment
[Complete/Targeted] Physical Exam
[Other Clin. Assess. components if on a different schedule]
Hematology
PT/PTT
Chemistry
Liver Function Tests
Urinalysis
Pregnancy Testing
Chest X ray
HIV-1 RNA (real time)

Appendix D: Lab Processing Flow Sheet/Template for Specimen Collection

Appendices: OPTIONAL

Protocol Version X.0

January 31, 2008

Page 5 of 34

NIAID Clinical Trial Protocol Template Version 2.0

TABLE OF CONTENTS

Page 3 of 34

1 August, 2006

APPENDICES

Clinical Trial Template with Sample Language

DHHS/NIH/NIAID/DCR/NCRS, Clinical Tial Template

Clinical Trial Template Sample Language Intra V.2.0 1-2008

Charles Hollman

2008-04-01

NIH/NIAID