The following policies apply to engagement in clinical research, clinical practice, and general activities performed within the NINDS intramural research program.
Standard Operating Procedures (SOPs)
|Title||SOP Category||Version||Initial Approval Date||Last Updated|
|Data Management||Clinical Research Policy||1.2||8/2/2022|
|Conducting a Clinical Trial Under IND or IDE When NINDS is the Sponsor||Clinical Research Policy||1||11/4/2020||11/4/2020|
|CTU Protocol Development Meeting||Clinical Research Policy||2||12/12/2014||12/3/2020|
|Data and Safety Monitoring (DSM)||Clinical Research Policy||1.1||1/9/2016||3/7/2017|
|DSMB Charter||Clinical Research Policy||1.1||1/9/2016||3/7/2017|
|DSMB Confidentiality Agreement||Clinical Research Policy||1.1||1/9/2016||3/7/2017|
|Optional DSM Memo to IRB||Clinical Research Policy||1.1||1/9/2016||3/7/2017|
|DSMB Interim Report||Clinical Research Policy||1.1||1/9/2016||3/7/2017|
|NINDS DSMB Support Request Form||Clinical Research Policy||1.1||1/9/2016||3/7/2017|
|Identification and Reporting of Protocol Related Events||Clinical Research Policy||1||10/20/2017|
|Initiating Emergency Medical Services to Patients Undergoing MRI Procedures with the NMR Center||Clinical Practice Policy||1||1/12/2022|
|NINDS P2 Parking Placard Assignments||NINDS General Policy||1||9/17/2021|
|Biostatistics Office||Clinical Research Policy||2||4/22/2016||9/20/2021|
|Protocol Navigator Regulatory Responsibilities||Clinical Research Policy||2||11/25/2019|
|Quality Assurance Audits||Clinical Research Policy||3.1||9/1/2010||2/1/2021|
|Quality Assurance Protocol Monitoring||Clinical Research Policy||2||2/1/2010||12/1/2014|
|Renewal of Clinical Privileges for Clinical Staff||Clinical Practice Policy||1.1||2/21/2020|
|Research Team Clinical Care Meetings||Clinical Research Policy||1.1||3/29/2017||3/30/2017|
Glossary of SOPs
Adverse Event: According to OHRP’s guidance document, Reviewing and Reporting Unanticipated Problems involving Risks to Subjects or Others and Adverse Events, an adverse event is any untoward medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in research, whether or not considered related to the subject’s participation in the research. In the context of FDA-required reporting, an AE means any untoward medical occurrence associated with the use of a drug or device in humans, whether or not considered drug or device related.
Adverse Reaction: Any adverse event caused by a drug. Adverse reactions are a subset of all suspected adverse events where there is reason to conclude that the drug caused the event.
ALCOA-C: The investigator/institution should maintain adequate and accurate source documents and trial records that include all pertinent observations on each of the site's trial subjects. Documentation of source data should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data should be traceable, should not obscure the original entry, and should be explained if necessary (e.g., via an audit trail).
Audit: A systematic and independent examination of trial-related activities and documents to determine whether a particular human research activity was conducted and the data were recorded, analyzed, and accurately reported according to specified requirements, such as protocol requirements, NIH IRB standard operating procedures (SOPs), FDA GCP (when applicable) and applicable regulatory requirements (OHSRP SOP 23.3 A).
Case Report Form (CRF): A case report form is a printed, optical, or electronic document designed to record all of the protocol-required information to be reported to the sponsor on each trial subject. (ICH E6, 1.11)
CDE Project (NINDS): The goal of the National Institute of Neurological Disorders and Stroke (NINDS) CDE Project is to develop data standards for neuroscientific clinical research. Central to this project is the creation of common definitions and metadata sets so that information (data) is consistently captured and recorded across studies.
CiSTAR (Clinical Informatics System for Trials and Research): is an electronic data capture system supported by NINDS IT. The database meets the requirements of a 21 CFR part 11 compliant system in that it:
- Ensures that data is attributable to a unique user with a secure password and role-based permissions
- Prevents changes from being made to the data by unauthorized users
- Provides safeguards to prevent unauthorized use of passwords and/or identification codes, and to detect and report any unauthorized attempts to the system
- Follows loss management procedures
- Includes a built in audit trail providing information about when the data was entered or changed and by whom
- Ensures user electronic signatures are unique to one individual
- Certifies that the electronic signatures are intended to be the legally binding equivalent of traditional handwritten signatures
- Imbeds within the electronic signature the printed name of the signer, the date and time of the signature and the meaning associated with the signature.
- Ensures that the electronic signature and handwritten signature are linked to their respective electronic records to ensure that the signatures cannot be excised, copied, or transferred to falsify an electronic record
Clinical Investigation: FDA regulations define a “clinical investigation” as any experiment that involves a test article (e.g. an investigational drug or device) and one or more human subjects. By definition, these are either: 1) experiments subject to requirements for prior submission to the FDA, or 2) experiments whose results are intended to be submitted later to, or held for inspection by, the FDA as part of an application for a research or marketing permit (See References for the links to definitions under 21 CFR 50.3(c)) and 21 CFR 56.102(c)).
For drugs, a clinical investigation is “any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects . ... an experiment is any use of a drug except for the use of a marketed [approved] drug in the course of medical practice” per 21 CFR 312.3(b). For devices, an “investigation” means a “clinical investigation or research involving one or more subjects to determine the safety or effectiveness of a device” per 21 CFR 812.3 (h).
Clinical Research Information System (CRIS): The NIH Clinical Center’s electronic medical record.
Clinical Trial: A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.
Clinical Trials Unit (CTU): As part of the Office of the Clinical Director, the Clinical Trials Unit (CTU) is a group of clinical research experts who collaborate to provide NINDS intramural investigators with support in developing and executing clinical research studies, as well as regulatory guidance. CTU members have extensive experience and knowledge regarding clinical research regulations, IRB and scientific review procedures, protocol navigation, protocol development, safety oversight, regulatory support, protocol auditing and monitoring, as well as statistical plan development and analysis.
Code of Federal Regulations (CFR): The Code of Federal Regulations is the codification of the general and permanent rules and regulations published in the Federal Register by the executive departments and agencies of the federal government of the United States. The CFR is divided into 50 titles that represent broad areas subject to federal regulation. Title 21 Chapter 1 is the portion of the Code of Federal Regulations that governs food and drugs within the US for the FDA, and 46 CFR 45 governs human subjects research.
Common Data Elements (CDEs): Standardized key terms or concepts, established so that they may be used in clinical research or in studies, to enhance data quality and so that the data can be used across sites and over time. The common data element is similar to an attribute; it functions as a key, which can then map to an associated value. Development and use of CDEs supports standardization of terms and facilitates data sharing so that data can be compared and combined across studies; research findings can then be generalized with respect to different research institutions, diverse populations, different regions, and interventions.
Conflict of Interest (COI): A conflict of interest occurs when a government matter, including clinical research, will have a direct and predictable effect on the financial interests of an individual or the individual’s spouse, minor children, general partner(s), or certain other organizations the individual serves as officer, director, trustee, general partner or employee, and entities with which the individual is negotiating for or has an agreement regarding prospective employment (18 USC § 208, 5 CFR Part 2640).
Contract Research Organization (CRO): A contract research organization is a person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor's trial-related duties and functions.
Corrective and Preventive Action (CAPA): A corrective action plan is a strategy for correcting or eliminating a problem that has already occurred or been identified. A preventive action plan defines the steps taken to eliminate the root cause of a problem to prevent it from recurring.
Covered Individuals: As per SOP 21, covered individuals are personnel who have independent decisional roles in conducting a specific covered research protocol. These individuals are influential in the design, direction, or conduct of a covered research protocol, or engaged in the analysis or interpretation of data. Individuals who participate only through isolated tasks that are incidental to the (for example, scheduling patient tests), and those individuals who support research of many protocols through the performance of routine patient care tasks are not covered individuals. Covered Individuals include the principal investigator, personnel whose resume or CV is provided to a sponsor, personnel listed on the FDA 1572 Form, and personnel engaged in human subjects research, including who obtain informed consent or who make decisions about research eligibility. Others who have decisional responsibilities that meet the definition of a covered individual, e.g. co- investigator, research nurse, associate investigators, or an individual who interprets or analyzes research data, are also covered individuals. The PI determines which individuals are “covered individuals” under SOP 21. When protocols contain sub-studies that ask a research question about a product, it is possible that only those individuals involved in decisional roles in the sub-study are “covered individuals.”
Data and Safety Monitoring entity (DSM entity): The individual or group designated as responsible for data and safety monitoring in the study’s Data and Safety Monitoring Plan.
Data and Safety Monitoring Plan (DSMP): A written description of the procedures for reviewing accumulated data in an ongoing research protocol to ensure the safety of research participants and the continuing validity and scientific merit of the protocol (OHSRP SOP 17.3 A). The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. The DSMP should establish guidelines for the assessment and progress of a clinical trial, at established intervals, to review safety data and the critical efficacy endpoints, and to recommend whether to continue, modify, or stop a trial. The mechanism for data and safety monitoring ranges from monitoring by the PI to monitoring by an Independent Medical Monitor (IMM), Safety Monitoring Committee (SMC), or a Data and Safety Monitoring Board (DSMB).
Data Management Plan (DMP): A document which describes how data are to be handled (collected and stored) both during the research study and after the study is completed and closed. A sound plan, managed from the initiation of the study to its completion, helps to ensure that research data are error-free and statistically sound to support the research conclusions. Preparing a data management plan before data are collected helps to ensure that data are collected and stored in the correct format, that prespecified quality control processes are identified, that the location of the stored data is described for future analyses, and ensures that data are clearly identified (mapped) and organized in a clear manner.
The management of clinical trial information (defined in ICH E6, 1.22) encompasses all study related data, materials, and documents. Clinical trial information includes all records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, as well as scans, x-rays, and graphic displays such as electrocardiograms and audiograms) that describe the data to be collected and the format in which the data will be stored.
Drug: A substance recognized by an official pharmacopoeia or formulary; a substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease; a substance (other than food) intended to affect the structure or any function of the body; or, a substance intended for use as a component of a medicine but not a device or a component, part or accessory of a device. Biological products are included within this definition.
Electronic Source Data: Electronic Source data are defined by the FDA as an electronic record as any combination of text, graphics, data, audio, pictorial, or other information represented in digital form that is created, modified, maintained, archived, retrieved, or distributed by a computer system. The are data initially recorded in electronic format. Electronic source data may include information in original records and certified copies of original records of clinical findings, observations, or other activities captured prior to or during a clinical investigation used for reconstructing and evaluating the investigation.
The “Guidance for Industry Electronic Source data in Clinical Investigations” https://www.fda.gov/media/85183/download provides in depth explanations and descriptions of electronically captured source data.
Essential Documents: Documents that individually and collectively permit evaluation of the conduct of a study and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and with all applicable regulatory requirements. (see Section 8 of ICH E6 (R2) “Essential Documents for the Conduct of a Clinical Trial” https://www.fda.gov/files/drugs/published/E6%28R2%29-Good-Clinical-Practice--Integrated-Addendum-to-ICH-E6%28R1%29.pdf).
Essential documents typically contained in a study Regulatory Binder and/or a Trial Master File (TMF) and/or study files, may include, but are not limited to, IRB approval memo, IRB member/board composition, study protocol, protocol amendments, approved consent form(s), advertisements used to recruit subjects, information given to participants, investigator’s brochure, clinical investigator’s curriculum vitae and other documents demonstrating qualifications, normal lab ranges, signed agreements between involved parties, sample labels for investigational products (IP), instructions for handling IP, shipping records for trial related materials, certificates of analysis of IP, deconding procedures, randomization lists, documentation of investigational product destruction, reports by independent data monitoring committees, signed consent documents, source documents, and completed case report forms.
FDA-Regulated Trials: “Any experiment that involves a test article and one or more human subjects that is either subject to requirements for prior submission to the Food and Drug Administration under section 505(i), or 520(g) of the act, or is not subject to requirements for prior submission to the Food and Drug Administration under these sections of the act, but the results of which are intended to be submitted to, or held for inspection by the Food and Drug Administration as part of an application for a research or marketing permit.” 21 CFR 50.3(c)
Good Clinical Practice (GCP): A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are protected (OHSRP SOP 23.3B).
Human Subject: A living individual about whom an investigator (whether professional or student) conducting research obtains data through intervention or interaction with the individual or obtains identifiable private information. A subject may be either a healthy human or a patient (per 21 CFR 50.3(g) and 21 CFR 56.102(e)). Regulations governing the use of human subjects in research extend to use of human organs, tissues, and body fluids from identifiable individuals as human subjects and to graphic, written, or recorded information derived from such individuals.
For drugs, a subject “means a human who participates in an investigation, either as a recipient of the investigational new drug or as a control. A subject may be a healthy human or a patient with a disease” per 21 CFR 312.3(b).
For medical devices, a subject “means a human who participates in an investigation, either as an individual on whom or on whose specimen an investigational device is used or as a control. A subject may be in normal health or may have a medical condition or disease” per 21 CFR 812.3(p).
ICH Guidelines: The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a project that brings together the regulatory authorities of Europe, Japan, and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of pharmaceutical product registration.
The purpose of ICH is to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines by recommending ways to achieve greater harmonization in the interpretation and application of technical guidelines and requirements for product registration. It is expected that harmonization will lead to a more economical use of human, animal and material resources, and the elimination of unnecessary delay in the global development and availability of new medicines while maintaining safeguards on quality, safety, and efficacy, and regulatory obligations to protect public health.
Investigational Device: A device that is the object of an investigation (21 CFR 812.3(g)).
Investigational Device Exemption (IDE): An IDE allows an investigational device (i.e. a device that is the subject of a clinical investigation) to be used in order to collect safety and effectiveness data required to support a premarket approval (PMA) application or a premarket notification [510(k)] submission to the Food and Drug Administration. An IDE is needed if a device is determined by the IRB to be a “significant risk device”.
Investigational New Drug (IND): A new drug or biological drug that is used in a clinical investigation. The term also includes a biological product that is used in vitro for diagnostic purposes (21 CFR 312.3(b)).
Institutional Review Board (IRB): “Any board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of, biomedical research involving human subjects. The primary purpose of such review is to assure the protection of the rights and welfare of the human subjects. The term has the same meaning as the phrase institutional review committee as used in section 520(g) of the act.” 21 CFR 56.102(g)
Intramural Research Training Award (IRTA) Traineeship: Traineeship established for the principal benefit of the participant and to provide opportunities for developmental training and practical research experience in a variety of disciplines related to biomedical research, medical library research and related fields.
IRTA: Research staff appointed using the Intramural Research Training Award traineeship mechanism for postdoctoral, pre-doctoral, post-baccalaureate trainees, and students.
Investigator: An “investigator” is any individual who is involved in conducting human subjects research (HSR) studies. Such involvement includes: (1) obtaining information about living individuals by intervening or interacting with them for research purposes; (2) obtaining identifiable private information about living individuals for research purposes; (3) obtaining voluntary informed consent of individuals to be subjects in research, or (4) studying, interpreting, or analyzing identifiable private information or data for research purposes (OHSRP SOP 19.3.1).
Investigator Brochure (IB): The IB is a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects. Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration, and safety monitoring procedures.
Lead Associate Investigator (LAI): The Lead Associate Investigator is the investigator who plays a leading role in the formulation, writing, and implementation of a clinical research protocol under the mentorship of the protocol’s PI.
Licensed Independent Practitioner (LIP): A physician, dentist, physician assistant or nurse practitioner who is permitted by law and is credentialed within the Clinical Center to provide care and services, within the scope of the individual’s license and delineation of privileges.
Monitoring: The act of overseeing the progress of a specific research study and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, NIH HRPP policies, standard operating procedures (SOPs), FDA GCP guidelines (when applicable), and the applicable regulatory requirement(s). This is a continuous process throughout the life of a research protocol (OHSRP SOP 23.3.1). According to the International Conference on Harmonization Regulations (ICH E6), the intent of protocol monitoring is to provide objective appraisal of trials to verify that: 1) the rights and well-being of human subjects are protected; 2) the reported trial data are accurate, complete, and verifiable from source documents, and 3) the conduct of the trial is in compliance with the currently approved protocol, GCP and applicable regulatory requirements. Protocol monitoring is an important component in ensuring human subject protection and the quality of clinical trial data.
Monitoring Plan: A written document providing a description of how the study will be monitored, how often, and the specific activities to be performed at each visit. Factors that are considered include: complexity of the protocol (e.g., number of activities performed during each visit), disease being evaluated (rate of disease progression or response to treatment), experience of the study staff, number of study subjects enrolled, and rate of enrollment. The monitoring plan may change as the study progresses, depending on these factors.
Multicenter Trials: A multicenter research trial is a clinical trial conducted at more than one medical center or clinic. NIH may be the coordinating site of a multicenter trial or may be one of several study sites.
NINDS Clinical Practice Committee (CPC): A NINDS committee tasked to review current practices and identify areas of improvement in relation to patient safety and clinical practice. The committee meets monthly to review compliance with Clinical Center guidelines, develop plans for implementation for new policies, and review SAEs as well as other events to determine if any further action is needed. The CPC may initiate root cause analyses as well as suggest M&M conferences.
NINDS Scientific Review Committee (SRC): Following Standards for Clinical Research within the NIH Intramural Research Program, as established by the NIH Clinical Center Medical Executive Committee, all protocols involving human subjects must undergo review of scientific content by an Institute’s scientific review committee. For NINDS, this function is carried out by the Scientific Review Committee (SRC). The role of the SRC is to review each NINDS research study for scientific merit and contribution to the research mission of NINDS and at time of initial submission. SRC is furthermore tasked to review the impact on central resources for each study.
Non-compliance: According to OHSRP Policy 802, non-compliance is defined as, “Failure of investigator(s) to follow the applicable laws, regulations, or institutional policies governing the protection of human subjects in research, or the requirements or determinations of the IRB, whether the failure is intentional or not.”
This may include, but is not limited to, the following:
- Failure to obtain IRB approval for research involving human subjects.
- Inadequate or non-existent procedures for informed consent.
- Inadequate supervision of research involving experimental drugs, devices, or procedures.
- Failure to follow an IRB-approved protocol.
- Failure to obtain prospective IRB approval for changes to a protocol.
- Failure to adhere to event reporting requirements.
- Failure to obtain continuing IRB review and approval.
Non-compliance may be further characterized as:
- Serious non-compliance - Non-compliance, whether intentional or not, that results in harm or otherwise materially compromises the rights, welfare and/or safety of the subject. Non-compliance that materially affects the scientific integrity or validity of the research may be considered serious non-compliance, even if it does not result in direct harm to research subjects.
- Continuing non-compliance - A pattern of recurring non-compliance that either has resulted, or, if continued, may result in harm to subjects or otherwise materially compromise the rights, welfare and/or safety of subjects, affect the scientific integrity of the study or validity of the results. The pattern may comprise repetition of the same non-compliant action(s), or different non-compliant events. Such non-compliance may be unintentional (e.g. due to lack of understanding, knowledge, or commitment), or intentional (e.g. due to deliberate choice to ignore or compromise the requirements of any applicable regulation, organizational policy, or determination of the IRB).
Non-Credentialed Investigators: Includes fellows and staff that hold a post-baccalaureate, post-doctoral or pre-doctoral degree and are engaged in human subjects research, yet are not eligible to hold clinical privileges in the Clinical Center.
Office of Human Subject Research Protection (OHSRP): OHSRP is an office within the NIH Intramural Research Program. The staff assists IRP investigators, research staff, the IRB and others to understand and comply with the ethical guidelines, regulatory requirements, and NIH policies and procedures for research involving human subjects.
Principal Investigator (PI): The Principal Investigator is responsible for the overall design and conduct of the IRB approved research protocol. In addition, the PI is responsible for assuring that all investigators are qualified by education, training, and experience needed to perform their delegated roles in the conduct of the study.
Protocol Deviation (PD): Any change, divergence, or departure from the IRB-approved research protocol (see OHSRP Policy 801).
Deviations may be further characterized as:
- Major Deviations - Deviations from the IRB-approved protocol that have, or may have the potential to, negatively impact, the rights, welfare or safety of the subject, or to substantially negatively impact the scientific integrity or validity of the study.
- Minor Deviations - Deviations that do not have the potential to negatively impact the rights, safety, or welfare of subjects or others, or the scientific integrity or validity of the study.
Quality Assurance Auditor: The NINDS Quality Assurance Auditor(s) is responsible for preparing for the internal QA audit, conducting the audit according to applicable standard operating procedures and regulatory requirements, reviewing preliminary observations with the Investigator, documenting observations in an audit report, and submitting that report to the Clinical Director and the Principal Investigator.
Quality Assurance and Data Management Office: The Quality Assurance and Data Management (QADM) Office is a division of the NINDS Clinical Trials Unit within the Office of the Clinical Director. The QADM Office assists the Clinical Neuroscience Program by disseminating NIH and FDA policy and guidelines and by providing assistance to the research staff to ensure compliance with good clinical practice guidelines. The QADM office provides oversight of protocol compliance by performing QA audits and QA monitoring of active protocols.
Quality Assurance Plan: The Principal Investigator is responsible for developing a quality assurance plan; describing who will perform independent QA monitoring, as well as the Institute and protocol specific requirements determining the frequency and composition of QA monitoring. The IRB requires that the quality assurance plan be described in the protocol. The QA plan may include: 1) independent QA protocol auditing (i.e., independent monitoring of the protocol at a single time point during the duration of the protocol); or 2) independent QA protocol monitoring (i.e., on-going monitoring of the protocol at multiple time points during the duration of the protocol). Per NINDS guidelines, non-FDA regulated trials may undergo independent QA protocol auditing, and FDA regulated trials require independent QA protocol monitoring.
Regulatory Binder: Each protocol must have a regulatory binder to maintain essential regulatory documents collected during the inception, continuation, and termination of the study. All original documents and all subsequent versions should be maintained in the regulatory binder for the duration of the study and for the designated time requirement post study termination. The Regulatory Binder may be kept in electronic or paper format. It should be maintained in a secure, limited-access location and kept confidential.
Research: A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Any activity which meets this definition constitutes “research” for purposes of this policy, whether or not conducted or supported under a program which is considered “research” for other purposes. For example, some demonstration and service programs may include research activities (see 45 CFR 46.102(d)).
Reportable Event: An event that occurs during the course of human subjects research that requires notification to the IRB. For the purposes of this policy, reportable events include non-compliance and unanticipated problems involving risks to subjects or others (also referred to as UPs), major deviations, deaths related or possibly related to research activities and new information that might affect the willingness of subjects to enroll or continue participation in the study.
Serious Adverse Event (SAE)* or Serious Adverse Drug Reaction (Serious ADR): Any untoward medical occurrence that at any dose:
- Results in death;
- Is life-threatening (places the subject at immediate risk of death from the event as it occurred);
- Requires inpatient hospitalization or prolongation of existing hospitalization;
- Results in persistent or significant disability/incapacity;
- Results in a congenital anomaly/birth defect; or
- Based upon appropriate medical judgment, may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition (OHSRP Policy 801).
*In IND-regulated research, additional terms including “serious suspected adverse reaction” (21 CFR 312.32(a)) and “Unanticipated adverse device effect” (21 CFR 812.3(s)) are used.
Significant risk device: An investigational device that: (1) Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject; (2) Is purported or represented to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject; (3) Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or (4) Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject (21 CFR 812.3(m)).
Source Data: All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).
Source Document: The ICH E6 document, section 1.52, defines source documents as "Original documents, data and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries of evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments) involved in the clinical trial."
Sponsor: “A person or other entity that initiates a clinical investigation, but that does not actually conduct the investigation, i.e., the test article is administered or dispensed to, or used involving, a subject under the immediate direction of another individual. A person other than an individual (e.g., a corporation or agency) that uses one or more of its own employees to conduct an investigation that it has initiated is considered to be a sponsor (not a sponsor-investigator), and the employees are considered to be investigators.” 21 CFR 50.3(e); see also 21 CFR 56.102(j).
Sponsor-Investigator: This refers to researchers who have the role of both “investigator” and “sponsor” as defined by the FDA. An “individual who both initiates and actually conducts, alone or with others, a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject. The term does not include any person other than an individual, e.g., corporation or agency” (see 21 CFR 312.3 and 21 CFR parts 50.3(f) and 56.102(k).)
STAMS (Specimen Tracking and Management System): STAMS is a web-based application built by NINDS Intramural IT, for sample tracking and management solutions for samples maintained in a repository. STAMS is accessible directly through the CiSTAR platform.
Stopping rules: Stopping rules identify specific triggers (i.e. events) that require some action. These are predetermined guidelines as to when enrollment, administration of study products or intervention or one or more study arms should be altered or stopped.
Study Statistician: The study statistician provides statistical expertise and leadership in the design and analysis of clinical research studies. Major responsibilities of study statisticians include contributing to study design of clinical trial (e.g. sample size calculations) from the early stages of clinical trials, writing statistical sections of the protocol, analyzing and interpreting clinical studies, preparing data deliverables for clinical study reports, participating in manuscript writing, assisting in follow-up activities including protocol amendments, and providing senior level peer review of work being accomplished by other biostatisticians.
Supervisor: A federal employee who is responsible directly for the clinical research activities of the IRTA or non-credentialed investigator.
Supervision (Level of): The act of providing oversight and direction to an individual or group. Level of supervision is determined by individual training (e.g., PhD) of the individual performing the procedure and the level of risk involved in the procedure or activity (minimal risk vs more than minimal risk).
- Readily Available Supervision - the supervisor can be directly contacted by phone or page and can physically arrive in the testing area within minutes.
- Immediately Available Supervision - the supervisor or LIP is physically available in the area where the procedure occurs.
Test Article: “Any drug (including a biological product for human use), medical device for human use, human food additive, color additive, electronic product, or any other article subject to regulation under the Federal Food, Drug and Cosmetic Act or under sections 351 and 354-360F of the Public Health Service Act (42 U.S.C. 262 and 263b-263n).” 21 CFR 50.3(j); see also 21 CFR 56.102(l).
Unanticipated Problem Involving Risks to Subjects or Others (UP): Any incident, experience, or outcome that meets all the following criteria:
- Unexpected (in terms of nature, severity, or frequency) given: (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied; AND
- Related or possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research), AND
- Suggests that the research places subjects, or others (which may include research staff, family members or other individuals not directly participating in the research) at a greater risk of harm (including physical, psychological, economic, or social harm) related to the research than was previously known or expected.
Unexpected: An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the investigator brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure listed only cerebral vascular accidents. "Unexpected," as used in this definition, also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the drug under investigation (21 CFR 312.32(a)).
Vulnerable Populations: 45 CFR 46.111(b) states the following regarding criteria for IRB approval of research “when some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons, additional safeguards have been included in the study to protect the rights and welfare of these subjects.”