Human Research at Temple University is a comprehensive and diverse enterprise that studies many important questions throughout our society. The human research activities provide valuable answers to a wide array of questions to address local, regional, statewide, national, and global areas of interest. Human Research can include social and behavioral investigations as well as experiments with new Medical Interventional treatments. Human Research at Temple University is governed by the Federal Government under the “Common Rule” 45 CFR 46 Sub" Part A.
The Office of Human Research Protections (OHRP) has established “Human Subject Regulations Decision Charts” that can be accessed at www.hhs.gov/ohrp/humansubjects/guidance/decisioncharts.htm. These guides are provided for Institutional Review Boards (IRBs), Institutions, Investigators, and others who decide if an activity is research involving human subjects. The Institutional Review Board at Temple University has final determination regarding review status of all projects at Temple.
A clinical research project includes numerous activities that present a variety of compliance Issues. It is important that individuals conducting clinical research have the awareness, sensitivity, and ability to apply their knowledge of the research regulations to protect human volunteers and maintain regulatory compliance. The historical landscape that shapes the clinical research environment today to the everchanging regulatory requirements when conducting clinical research are designed to ensure all entities are protected.
1.1 Defining Human Subject Research
The National Institute of Health provides the following definitions:
Research:
A systemic investigation, including Research development, testing and evaluation, designed to develop or to contribute to generalizable knowledge. As examples, the following are human research; case reports, retrospective evaluation, case-controlled evaluation of disease and incidence, prospective randomized trials and data collected to support an application to the FDA.
Clinical Research
(1) Patient-oriented research. Research conducted with human subjects (or on material of human origin such as tissues, specimens and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects. Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual. Patient-oriented research includes: (a) mechanisms of human disease, (b) therapeutic interventions, (c) clinical trials, or (d) development of new technologies.
(2) Epidemiologic and behavioral studies.
(3) Outcomes research and health services research. Note: Studies falling under Exemption 4 for human subject’s research are not considered clinical research by this definition.
Human Subject
The HHS regulations “Protections of Human Subjects” (45 CFR Part 46, administered by OHRP) define a human subject as a living individual about whom an investigator conducting research obtains:
Data through intervention or interaction with the individual or
Identifiable Private Information
Intervention
Includes both Physical Procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subjects environment that are performed for research purposes (45 CFR 46.102(f)).
Interaction
Includes communication or interpersonal contact between Investigator and Subject (45 CFR 46.102(f)).
Individually Identifiable Private Information.
According to its guidance for use of coded specimens, OHRP generally considers private information or specimens to be individually identifiable as defined at 45 CFR 46.102(f) when they can be linked to specific individuals by the investigator(s) either directly or indirectly through coding systems. Conversely, OHRP considers private information or specimens not to be individually identifiable when they cannot be linked to specific individuals by the investigator(s) either directly or indirectly through coding systems.
Coded. With respect to private information or human biological specimens, coded means that:
Identifying information (such as name or social security number) that would enable the investigator to readily ascertain the identity of the individual to whom the private information or specimens pertain has been replaced with a number, letter, symbol or combination thereof (i.e., the code); and
A key to decipher the code exists, enabling linkage of the identifying information with the private information or specimens.
Research that involves only coded private information/data or coded human biological specimens may not constitute human subjects research under the HHS human subjects regulations (45 CFR Part 46) if:
The specimens and/or information/data are not obtained from an interaction/intervention with the subject specifically for the research; and
The investigator(s) cannot readily ascertain the identity of the individual(s) to whom the coded private information or specimens pertain (e.g., the researcher's access to subject identities is prohibited).
A prospective biomedical or behavioral research study of human subjects that is designed to answer specific questions about biomedical or behavioral interventions (drugs, treatments, devices, or new ways of using known drugs, treatments, or devices).
Clinical trials are used to determine whether new biomedical or behavioral interventions are safe, efficacious, and effective.
Behavioral human subjects research involving an intervention to modify behavior (diet, physical activity, cognitive therapy, etc.) fits this definition of a clinical trial.
Human subjects research to develop or evaluate clinical laboratory tests (e.g. imaging or molecular diagnostic tests) might be considered to be a clinical trial if the test will be used for medical decision making for the subject or the test itself imposes more than minimal risk for subjects.
Biomedical clinical trials of experimental drug, treatment, device or behavioral intervention may proceed through four phases:
Phase I- test a new biomedical intervention in a small group of people (e.g., 20-80) for the first time to evaluate safety (e.g., to determine a safe dosage range and to identify side effects).
Phase II clinical trials - study the biomedical or behavioral intervention in a larger group of people (several hundred) to determine efficacy and to further evaluate its safety.
Phase III clinical trials - investigate the efficacy of the biomedical or behavioral intervention in large groups of human subjects (from several hundred to several thousand) by comparing the intervention to other standard or experimental interventions as well as to monitor adverse effects, and to collect information that will allow the intervention to be used safely.
Phase IV clinical trials - are conducted after the intervention has been marketed. These studies are designed to monitor effectiveness of the approved intervention in the general population and to collect information about any adverse effects associated with widespread use.
NIH-Defined Phase III Clinical Trial.
For the purpose of the Guidelines an NIH-defined Phase III clinical trial is a broadly based prospective Phase III clinical investigation, usually involving several hundred or more human subjects, for the purpose of evaluating an experimental intervention in comparison with a standard or controlled intervention or comparing two or more existing treatments. Often the aim of such investigation is to provide evidence leading to a scientific basis for consideration of a change in health policy or standard of care. The definition includes pharmacologic, non-pharmacologic, and behavioral interventions given for disease prevention, prophylaxis, diagnosis, or therapy. Community trials and other population-based intervention trials are also included.
Autopsy Materials-
The use of Autopsy Materials is governed by applicable federal, state, and local law and is not directly regulated by 45 CFR Part 46. However the TU IRB must be consulted prior to collection of materials.
PHS definition of a 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.
1.2
Study Team –Defining Roles and Responsibilities
A human subject research study team can be comprised of a single individuals or a complex network of professionals collaborating to complete a research project. The human subject research team must be sensitive to the core ethical principles and adhere to the federal, local, and institutional policies when conducting clinical research. The Principal Investigator is responsible for the conduct of clinical research and is held accountable for his/her study team.
The OHRP considers the term investigator to include anyone involved in conducting the research.
Principal Investigator - A person qualified and responsible for the conduct of a clinical research project at the Institution. The Principal Investigator must ensure that all individuals on the clinical research study team are appropriately qualified to perform delegated tasks and properly trained on the research protocol. The Principal Investigator must ensure appropriate facilities are available and that the study team is able to properly communicate with the Principal Investigator during the course of the Investigation.
Conducting Clinical Research using an FDA regulated Product- The Principal Investigator would be listed in Box #1 of the FDA form 1572. The Principal Investigator would sign the 1572 document on page 2 and commits to all requirements of Box #9.
Sub-Investigator- Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g. physicians, residents, research fellows, and other professional trained individuals Pharm.D., Nurse Practitioner). This individual must be properly qualified an trained to perform assigned tasks during the trial.
Conducting Clinical Research using an FDA regulated Product these individual would be listed in box #6 of the FDA form 1572
Clinical Research Coordinator (CRC) – The research coordinator is often a nurse or qualified individual to assist with the day to day activities in managing the clinical research project. A research coordinator should be well trained in the federal and institutional requirements for conducting a clinical research project and assists the investigator with compliance when conducting the trial. A clinical research coordinator is an unwritten requirement of sponsor’s when conducting a clinical research project using an FDA regulated compound.
Conducting Clinical Research using an FDA regulated Product- It is strongly recommended that the research coordinator not be listed in box #6 of the FDA form 1572 when conducting a trial at Temple University unless the person is qualified to perform medically related evaluations and treatment follow up without the supervision of a physician. An individual may be listed as a sub-investigator if performing both roles and is qualified to do so.
A clinical research coordinator may perform the following activities during the conduct of a trial
Assist with Recruitment of Study Participants
Participate in the Informed Consent Process
Organize and Maintain Regulatory Documentation
Coordinate Study Procedures and Follow Up Visits
Serve as a liaison for subjects, investigators, IRB, Sponsor, and health care providers
Collect and Report Adverse and Serious Adverse Events
Sponsor – An Individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial.
Sponsor Investigator- An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to or used by a subject. The term does not include any person other than an individual (e.g. it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator.
Key Research Personnel- This is a term for NIH grant submissions
Additional Study Team Members may include:
Co-Principal Investigator
Regulatory Specialist
Data Manager
Laboratory Assistant/Phlebotomist
Statistician
Data and Safety Monitoring Board
Medical Monitor
Project Manager
Clinical Research Associate (CRA or Monitor)
Clinical Research Organization
All faculty and staff participating as a study team member for the conduct of a clinical research at Temple University using human subject must complete the Institutional Requirement for “Human Subject Protections Training” administered by the Institutional Review Board.
1.3
Glossary of Terms for Clinical Research
There are numerous terms and definitions specific to clinical research and are universally accepted when conducting a clinical trial. This is an abbreviated Glossary of Terms that are relevant when conducting clinical research.
Adverse Experience (AE):
An AE is defined as any unfavorable and unintended sign (including significant abnormal laboratory findings), symptom, or disease temporally associated with the use of study treatment(s) during a clinical study, whether or not considered related to the use of the study treatment(s).
An AE includes:
Conditions which appear after initial administration of the study treatment(s)
Pre-existing conditions which are present prior to the study treatment(s) and worsen after the administration of study treatment(s)
Any historical conditions not present prior to initiation of study treatments, which reappear following the administration of study treatment(s)
Case Report Form (CRF):
A record of clinical study observations and other information completed for each subject in a study. The data may be recorded on paper or electronically on a computer.
Clinical Protocol:
Document describing a clinical study and how it is to be conducted. A protocol includes the objectives of the study, the study design, a description of the test article(s) and dosage, the experimental procedure, handling of adverse reactions, how the results will be analyzed, and consent and clearance provisions.
Clinical Research Associate (CRA):
The individual responsible for carrying out on-site monitoring, data verification, and reporting on the progress of the study.
Clinical Study/Trial:
Human studies designed to distinguish a drug's effect from other influences, for example, a spontaneous change in disease progression or in the effect of a placebo (an active substance that looks like the test drug). Such studies conducted in this country must be under an approved IND under the guidance of an institutional review board and in accord with FDA rules on human studies and informed consent of participants.
Code of Federal Regulations (CFR):
Document that contains FDA published regulations which can be found in Title 21CFR.
Curriculum Vitae (CV):
A formal listing of a person's academic background and training. For investigators and subinvestigators this includes a listing of medical school, residencies, fellowships, and publications.
Data Management:
The process of handling clinical study data. Data management begins with the submission of the CRF to the sponsor and includes activities regarding database creation, data entry, review, coding, data editing, data QC, archiving and reporting of the database.
Documentation:
All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records; and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken.
Essential Documents:
Documents "which individually and collectively permit evaluation of the conduct of a trial and the quality of data produced." (ICH Guideline for GCP 8.1) Examples: investigator's brochure, protocol, informed consent form, monitoring reports, CRFs, source documents, IRB/ERC approvals.
FDA 1572:
Signed agreement from the investigator required for studies conducted under U.S. IND which indicates that the requirements for conducting the study, including the investigator's obligations are understood by the investigator and that the qualifications to conduct the trial are met. Receipt of the FDA 1572 by the sponsor is required prior to shipment of any investigational drugs to investigator.
GCP (Good Clinical Practices*):
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.
ICH Guidelines:
A set of guidelines developed by the International Conference on Harmonization made up of industry and government representatives from the U.S., Japan and Europe designed to govern the worldwide development of drugs in conformance with accepted practices and ensure the mutual acceptance of the data.
IND/Investigational New Drug Application (Claimed Notice of Investigational Exemption):
(Code of Federal Regulations, Title 21, Part 312) Documentation that must be submitted to the FDA before a new drug (or biologic) can be shipped interstate for human testing. (In practical terms, all major companies file an IND, and await the 30-day review period before first administration of a compound to man.) This includes all appropriate evidence that clinical investigations can be performed with reasonable safety to the subject or patient (first animal safety test, pharmacology, manufacturing procedures, and proposed first protocol). Following initial filing, the IND becomes a "central file" for information on the drug/biologic (new formulations and/or indications on the compound may require an additional separate IND to be filed).
All relevant subsequent information (amendments) should be forwarded, e.g., final study reports, serious adverse experience reports, new protocols (both clinical and non clinical) and a yearly progress report summarizing the last year's information and proposed plan for the future year.
Informed Consent:
A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate. Informed consent is documented by means of a written, signed, and dated informed consent form. (
Informed Consent Fom)A document approved by the Institutional Review Board/ Ethics Review Committee (IRB/ERC) which describes to a potential subject the aims, methods, anticipated benefits, and potential hazards of an investigational study in a language he/she understands.
Investigator's Brochure (IB):
A document containing information about the investigational drug including a description of the drug formulation, a summary of toxicological and pharmacological effects of the drug, a summary of the pharmacokinetics of the drug, a summary of safety and effectiveness, and a description of possible risks and side effects. The IB must be updated whenever there is relevant new information about the drug.
NDA (New Drug Application):
The marketing application in the US for a new drug, containing all pre-clinical, clinical, and manufacturing data, plus the proposed labeling of the study drug.
Safety Reports (IND Safety Reports):
Expedited of significant safety information for all AEs that are determined to be: serious; unexpected; and associated with the use of an investigational drug (related). These reports must be submitted to regulatory authorities and all clinical investigators within 15 calendar days (ICH). For those AEs that result in death or if the AE is life threatening, a telephone/fax report must also be made to the regulatory authority within 7 calendar days (ICH).
Serious adverse experience:
Any adverse experience occurring at any dose that results in any of the following outcomes: death, a life threatening adverse experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one. 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.
Source Documents:
Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subject's diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, 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).
