- The Basic Ethical Principles of Conducting Research with Human Participants
When we talk about conducting research ethically and having ethics, what does "ethics” mean? In the simplest terms, ethics are the norms for conduct that distinguish between acceptable and unacceptable behavior. So, when we talk about conducting research ethically, we are talking about the normal conduct that is acceptable when conducting research.There are numerous resources that guide us in understanding these norms of conduct, including, The Belmont Report, Good Clinical Practice Guidelines and even the Federal regulations. This section provides resources on these norms for conduct that guide research with human participants.
The Belmont Report
The Belmont Report is a report created by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The purpose is to protect participants in clinical trials and research studies. The Belmont Report highlights 3 principles imperative to conducting ethical research which are justice, beneficence and respect for persons.
Researchers should minimize risks to study participants by utilizing procedures that are consistent with sound study design. Studies should be designed to ensure the research will likely develop or contribute to generalizable knowledge. In addition, researchers should document in their IRB application and support materials how the potential risks of participation are reasonable in relation to anticipated benefit and that the expected results of the research justify proceeding.
Office for HumanResearch Protections Educational Videos including:
Research Use of Human Biological Specimens and Other Private Information
Reviewing and Reporting Unanticipated Problems and Adverse Events
General informed Consent Requirements
Institutional Review Board (IRB) Membership
Complex Issues with Research Involving Vulnerable Populations
IRB Records (Parts One and Two)
- Fundamentals of Conducting Clinical Research: Good Clinical Practice
Good Clinical Practice (GCP): GCP is an international quality standard that is provided by International Conference on Harmonisation (ICH). GCP Guidelines include standards on how clinical trials should be conducted, defines the roles and responsibilities of clinical trial sponsors, clinical research investigators, and monitors and includes protections for human research participants in clinical trials.
To harmonize the various international drug development regulations and guidelines.
To provide a unified standard to facilitate the mutual acceptance of clinical data by the mutual acceptance of clinical data by the regulatory authorities and remove redundancy/duplication in development and review process.
Good Clinical Practice is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. Public assurance that the rights, the rights, safety, and well-being of trial participants are protected is consistent with the Declaration of Helsinki andThe Belmont Report and results in credible data.
ICH – GCP Guidelines
Collaborative Institutional TrainingInitiative (CITI) GCP course (Note you must login to CITI to complete the course.)
Good Clinical Practice: A Question & Answer Reference Guide
Addresses the most frequently asked questions in clinical research. Provides FDA supported interpretation of regulations in answering the questions. Updated yearly.
CenterWatch’s training guides are “must-read” resources for those interested in clinical research and for seasoned professionals seeking to better understand their roles and improve the management of their clinical trials operations in a safe and ethical manner.
Becoming a Successful Clinical Research Investigator Guide to Patient Recruitment and Retention
Protecting Study Volunteers in Research – 4th edition
The CRC’s Guide to Coordinating Clinical Research
Go to http://store.centerwatch.com/c-29-training-guides.aspx to purchase your own copy or contact the UH Clinical Research Center to check out a copy.
Responsible Conduct of Research, A. Shamoo & D. Resnick, 2003 (Oxford: Oxford).
- Federal Guidelines for Research Involving Human Subjects
All research conducted at University Hospitals Health System, and its affiliates, is governed by Federal and state regulations pertaining to human research protections, as well as other guidance and local policies and procedures.
The UH IRB regulates human subject research under the following U.S. Code of Federal Regulations: 21 CFR Parts 50 and56, 45 CFR Part 46, Subpart A (The Common Rule) and 45 CFR 160 and 164 (HIPAA Privacy Rule). Regulations that govern investigational new drugs (INDs) are found in 21 CFR Part 312; biologics are found in 21 CFR Part 600 and devices are found in 21 CFR Part 812.
A Federalwide Assurance (FWA) is an institution or organization's assurance to the Federal government that human subject research conducted at that site is in compliance with Federal regulations pertaining to the protection of human subjects.
The UH IRB’s FWA is FWA00003937.
The Assurance states that all research involving human subjects that is conducted by UH staff or by researchers who fall under the purview of UH, or on UH premises or under its sponsorship, whether supported by Federal funds or not, must be reviewed and approved by the UH Cleveland Medical Center IRB. This policy also applies to protocols sponsored by UH staff conducting research at other hospitals, institutions, or community groups. In order to approve human subject research in accordance with Federal regulations the UH IRB must determine that all of the following requirements are satisfied:
- Risks to subjects are minimized.
- Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result.
- Selection of subjects is equitable.
- Informed consent will be sought from each prospective subject or the subject’s legally authorized representative.
- Informed consent will be appropriately documented.
- When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of participants.
- When appropriate, there are adequate provisions to protect the privacy of participants and to maintain the confidentiality of data.
- UH Research Policies and Procedures
Any UH clinician or staff involved in conducting human subject research at UH must read and be familiar with the following institutional policies.
UH System– Key Research Policies
R-39 Clinical Investigation
- Research activities involving human subjects, discarded tissue, or the collection of data, regardless of the location of the activities or source of funding, must have protocols describing such activities approved by the IRB prior to initiation.
- Clinical investigations will have the agreement(s) and budget(s) related to such investigations approved by the Grants and Contracts Office prior to initiation.
- Human research may undergo monitoring to assure the protection of human research participants and allegations of non-compliance will be investigated.
- Misconduct in research must be reported, whether observed, suspected or apparent, to the director of the department in which the research misconduct occurred.
CP-7 – Investigational Drugs
- Investigators must ensure that investigational drugs are stored in and dispensed from Pharmacy Services unless an Investigational Drug Services Exception Request has been approved.
- A copy of the research participant’s signed consent form is to be included in the patient’s medical record.
R-40 Research Misconduct
- Possible research misconduct must be reported immediately.
For a complete list of UH Research policies see Research section of the policies on the UH intranet.
For a complete list of UH IRB Policies click here.
UH IRB Policies address the following areas:
Actions for Approved Protocols
Research Standard Operating Procedures
Click here for a complete list of effective and bResearch SOPs.
Standard Operating Procedures (SOPs) are uniformly written procedures, with detailed instructions to record routine operations, processes and practices followed within a business organization. In clinical research, SOPs help define the group’s (e.g., unit, division, department, institution, etc.) standard practices and daily processes conducted to assure execution of research tasks in accordance with institutional, state and federal guidances.
SOPs should contain adequate detail to clearly guide research staff through a particular procedure and thereby establish uniformity in the everyday functions of the department. Each SOP should have a specific aim but be written in a general format that can be easily followed by a broad audience. By laying out defined processes, the primary function of an SOP is to specifically avert procedural deviations.
Distribution, education and training on new departmental SOPs should be consistent. It is important to document the date research staff have been appropriately trained and are deemed competent to perform new SOPs implemented by the department. Research staff should be monitored consistently and receive refresher training at regular intervals to ensure compliance.
Existing SOPs should be reviewed at regular intervals to reassess applicability of the policy. Annual review is recommended and review prior to sponsor interactions is encouraged.
- Conducting FDA Regulated Studies & FDA Guidance Documents
The following list of the USFood and Drug Administration (FDA) Guidance documents represents the Agency’s current thinking on good clinical practice (GCP) and the conduct of clinical trials. For a complete list of all available FDA Guidance documents click here.
General Information Sheet Guidance
- "Off- Label" and Investigational Use Of Marketed Drugs, Biologics, and Medical Devices – Information Sheet – 01/1998
- Sponsor – Investigator – IRB Interrelationship – Information Sheet – 01/1998
Drugs and Biologics Information Sheet Guidance
- Drug Study Designs – Information Sheet – 01/1998
- Emergency Use of an Investigational Drug or Biologic – Information Sheet – 01/1998
- Treatment Use of Investigational Drugs – Information Sheet – 01/1998
Medical Devices Information Sheet Guidance
- Medical Devices, Frequently Asked Questions About – Information Sheet (PDF – 266KB) – 01/2006
- Significant Risk and Nonsignificant Risk Medical Device Studies – Information Sheet (PDF – 266KB) – 01/2006
General Guidance Documents
- Data Monitoring Committees for Clinical Trial Sponsors, The Establishment and Operation of Clinical Trial – 03/2006
- Financial Disclosure by Clinical Investigators – 05/2011
- Financial Relationships and Interests in Research Involving Human Subjects
- Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects (PDF – 163KB) – 10/2009
Institutional Review Boards (IRBs) and Informed Consent Guidance Documents
- Responsibilities of a Principal Investigator
The principal investigator is ultimately responsible for the conduct of the study and for assuring compliance with IRB policies and procedures and with local, state and Federal regulations pertaining to human subject protections.
Even though a principal investigator may delegate specific tasks to other members of the research team, he or she cannot delegate the responsibility for ensuring that those tasks are completed according to institutional and Federal regulations. The following is a list of responsibilities a principal investigator must be aware of.
The primary responsibility of the principal investigator is to acknowledge and accept the responsibility and ethical obligations for protecting the rights and welfare of human research participants in compliance with current Federal regulations and IRB requirements governing human subject research.
The principal investigator is the ultimate protector of the research participant’s rights and safety. He or sheis obligated to:
- Ensure that all human subject research receives IRB approval before the research starts
- Submit a research project for IRB review
- Conduct study In accordance with the approved protocol and consent document
- Personally conduct or supervise the study
- Recruit participants in an ethical manner
- Ensure that the requirements for obtaining informed consent are met
- Maintain a protocol file of human research project documents
- Comply with Federal and institutional time periods for record retention
- Maintain records for non-FDA projects
- Respond to participants who have an adverse event
- Keep subjects fully informed of any new information
- Provide reports as required by the sponsor and by the IRB
- Make records available for inspection
- Ensure accountability of investigational drugs, devices, or biologics
- Protect the privacy of research participants and maintain the confidentiality of data
- Consent designees (when applicable)
- Address participant complaints or concerns
- Establish a data and safety monitoring plan
- Ensure Sponsor-Investigator responsibilities are upheld when he/she is an Investigational New Drug (IND) or Investigational Device Exemption (IDE) holder from the FDA.
Investigators have a responsibility to protect human subjects and ensure the integrity of the data from clinical investigations. The following resources provides detailed information on the investigator’s responsibility to 1) supervise a clinical study in which some study tasks are delegated to employees or colleagues of the investigator and 2) to protect the rights, safety, and welfare of study participants.
Presentation Archive: InvestigatorResponsibilities in FDA Regulated Research (6/2012)
FDA Form 1572
The ‘1572’ is a Federal form and is the statement of the investigator that he/she will abide by the Federal guidelines set forth in the Code of Federal Regulations for the use of drugs in an investigational setting.
Presentation Archive: About FormFDA 1572 Statement of Investigator (7/2009)
FDA Guidance: Frequently Asked Questions – Statement of Investigator
FDA Clinical Investigator Course
To help develop a cadre of well-trained investigators, FDA has launched a Clinical Investigator Training Course targeted at medical professionals (experts who sign FDA Form 1572 before participating in an investigation). The 3-day course includes lectures given by senior FDA experts and guest lecturers from industry and academia, providing FDA's perspectives on new safety concerns, adverse event monitoring, compliance with legal and ethical obligations of clinical research, and acceptable scientific and analytic standards in clinical study design and conduct.
The annual courses, held in November, cover topics ranging from basic concepts of clinical trial design and how to review clinical data for sources of bias and errors to what to look for in drugs being studied in a clinical trial. Click here for a link to view videos, slides and transcripts from past sessions.
FDA Clinical Investigator Course 2012
Access videos, slides and transcripts from the FDA’s annual Clinical Investigator Course. Topics include:
The Clinical Trial Protocol
FDA and the Regulation of Clinical Trials
Understanding the Investigator Brochure – Non-Clinical and Phase 1 Studies
Early Clinical Studies Session
Putting It All Together – Application and Compliance Issues
Breakout Sessions for Drug/Device/Biologics
Safety of Clinical Trials and Special Populations
FDA Clinical Investigator Course 2011
Access videos, slides and transcripts from the FDA’s annual Clinical Investigator Course. Topics include:
Good Clinical Practice – Key Topics
Investigator Responsibilities – Parts 1 and 2
Informed Consent and Ethical Considerations
CMC (Chemistry, Manufacturing and Controls – Quality) and the Investigator Brochure (Drugs and Biologics)
Pharmacology/Toxicology in the Investigator Brochure
FDA Perspective on International Studies
The Design of Clinical Trials
Clinical Trial Endpoints
Issues in Clinical Trial Designs for Devices
The Analysis of Investigator Data, Sources of Bias and Error
How to prepare an IND/IDE application
- Investigational New Drug Applications (IND) – What you should know
An IND is required for a clinical study if it is intended to support a:
- New indication.
- Change in the approved route of administration or dosage level.
- Change in the approved patient population (e.g. pediatric) or a population at greater or increased risk (elderly, HIV positive, immunocompromised).
- Significant change in the promotion of an approved drug.
Initiating an Investigational New Drug Application
There are three IND types:
- An Investigator IND is submitted by a physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. A physician might submit a research IND to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population.
- Emergency Use IND2 allows the FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND in accordance with 21CFR , Sec. 312.233 or Sec. 312.34.4 It is also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.
- Treatment IND5 is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.
The IND application must contain information in three broad areas:
- Animal Pharmacology and Toxicology Studies – Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans. Also included are any previous experience with the drug in humans (often foreign use).
- Manufacturing Information – Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product. This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug.
- Clinical Protocols and Investigator Information – Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks. Also, information on the qualifications of clinical investigators – professionals (generally physicians) who oversee the administration of the experimental compound--to assess whether they are qualified to fulfill their clinical trial duties. Finally, commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations.
Responsibilities of an Investigator Who is also the Holder of the IND
Investigators who are IND holders are responsible for (this is a list of general responsibilities, and shouldnot be considered all inclusive):
- Preparing and submitting an annual renewal to the FDA.
- Understanding when a protocol amendment should be filed with the FDA.
- Filing FDA Safety Reports: when required, how to complete and where to send them.
- Responding to FDA protocol inquiries.
- Understanding Forms FDA 1571, 3455 and 1572 and how and when to update them.
- Understanding FDA Guidance documents.
Investigational New Drug (IND) Application– Information from the FDA
Presentation Archive: How Do You Know When and IND is Required? (4/2012)
Presentation Archive: Maintaining your IND with the FDA: Keys for Success (7/2012)
UH Investigator Initiated Research Checklist – Good Clinical Practice (GCP) Guidance
- Investigational Device Exemptions (IDE) – What you should know
An investigational device exemption (IDE) allows the investigational device to be used in a clinical study in orderto collect safety and effectiveness data to support a Premarket Approval (PMA) application or a Premarket Notification[510(k)] submission to the FDA.
Clinical evaluation of devices that have not been cleared for marketing requires:
- An IDE approved by the Institutional Review Board (IRB). If the study involves a significant risk device, the IDE must also be approved by FDA
- Informed consent from all patients
- Labeling for investigational use only
- Monitoring of the study and
- Required records and reports.
Responsibilities of an Investigator Who is also the Holder of the IDE
Investigators who are IDE holders are responsible for (this is a list of general responsibilities, and should not be considered all inclusive):
- Preparing and submitting an annual renewal to the FDA.
- Understanding when a protocol amendment should be filed with the FDA.
- Filing FDA MedWatch Reports: when required, how to complete and where to send them.
- Responding to FDA protocol inquiries.
- Understanding the Investigator Agreement and Form FDA 3455 and how and when to update them.
- Understanding FDA Guidance documents.
Investigational Device Exemptions – Information from the FDA
Presentation Archive: How Do You Know When an IDE is Required? (3/2012)
Presentation Archive: Maintaining Your IDE with the FDA: Key for Success (7/2012)
- Conducting Your Study at Multiple Sites Locally – The Multi-Institutional FacilitatedInstitutional Review Board (IRB) Process
The online, electronic Facilitated Review Hub is a collaborative effort within the Cleveland Clinical and Translational Science Collaborative (CTSC) to provide a centralized review and approval process for human subject research involving two or more CTSC affiliated institutions and its participating medical research facilities. Investigators at Case Western Reserve School of Medicine (CWRU), Cincinnati Children’s Hospital Medical Center (CCHMC), Cleveland Clinic (CC), Nationwide Children’s Hospital (NCH),The MetroHealth System (MHS), The Ohio State University (OSU), University Hospitals Cleveland Medical Center (UHCMC), and University of Cincinnati (UC) are eligible to utilize the ‘Hub’. Once a protocol is approved at one CTSC institutional review board (IRB of Record), it can be submitted to the Hub for a Facilitated review by the other participating institutions (Named IRBs).
Researchers can register to access the IRB hub at https://mhirb.metrohealth.org/irb
- Submitting to the Institutional Review Board (IRB)
Click here for an easy to follow flow chart of what you need to do and what you should expect in preparing to begin your research study. The UH Clinical Research Center is here to assist throughout this entire process, please contact the IRB Administration Office at 216-844-1529 with any questions.
- Important Definitions Relating to Human Subject Research
Clinical Investigation (FDA) : Any experiment that involves a test article and one or more human subjects. The terms research, clinical research, clinical study, study, and clinical investigation are deemed to be synonymous.
Human Subject (DHHS) : A living individual about whom an investigator (whether professional or student) conducting research obtains (1) data through intervention or interaction with the individual or (2) identifiable private information.
Human Subject (FDA) : An individual who is or becomes a participant in research either as a recipient of the test article or on whose specimen a test article is used or as a control. A subject may be a healthy individual or a patient.
Research (DHHS) : A systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge.
Protected Health Information – PHI is individually identifiable health information, including demographic data that is collected from an individual, and:
- is created or received by a health care provider, health plan, public health authority, employer, life insurer, school /university, or health care clearing house; AND
- relates to past, present or future physical or mental health or condition of the individual; or the provision of health care to an individual; or the past, present, or future payment for the provision of health care to an individual; AND
- identifies the individual or where there is a reasonable basis to believe the information can be used to identify the individual; AND
- is transmitted or maintained in any form or medium, whether electronic, paper or oral.
Subject Identifiers under HIPAA include: (1) Names (including the patient’s name and names of other individuals connected to the patient); (2) Geographic subdivisions smaller than a state (zip-code, street address, etc); (3) All elements of a date (except year) including birth date, admission date, discharge date, date of death, and all ages over 89); (4) Telephone numbers; (5) Fax numbers; (6) E-mail address; (7) Social security number; (8) Medical record number; (9) Health plan beneficiary numbers; (10) Account numbers; (11) Certificate/license numbers; (12) Vehicle identifiers and serial numbers including license plates; (13) Device identifiers and serial numbers; (14) Web universal resource locators (URLs); (15) Internet protocol (IP) address numbers, (16) Biometric identifiers including fingerprints and voice prints; (17) Full face photographic (or comparable) images; (18) Any other unique identifying number, characteristic, or code unless otherwise permitted by the Privacy Rule for re-identification (UH Policy R-3 – Uses and Disclosures of PHI for Research Purposes)
Test Article (FDA): Any drug for human use, biological product for human use, medical device for human use, human food additive, color additive, electronic product, or any other article for human use.
- Professional Research Organizations
Association of Clinical Research Professionals (ACRP)
Mission: To provide global leadership to promote integrity and excellence for the clinical research profession. The Association of Clinical Research Professionals (ACRP) is the primary resource for clinical research professionals in the pharmaceutical, biotechnology and medical device industries, and those in hospital, academic medical centers and physician office settings.
ACRP Certification is granted in recognition of verified work experience and successful performance on a multiple-choice exam. ACRP currently offers three Certification exams, one for Clinical Research Associates/CRAs (Monitor), one for Clinical Research Coordinators/CRCs (Site), and one for Physician Investigators/PIs (MD). The exams are based on the industry's largest validated job analysis to ensure the exams reflect the frequency and importance of what CRAs, CRCs, and PIs do in the clinical research process.
CRA, CRC and PI exams are offered in March and September every year. Exams will evaluate your expertise on topics and regulations specifically related to your ability to make decisions in specific scenarios. For more information on each of the exams and the deadlines for registration, visit the ACRP website at www.acrpnet.org.
Public Responsibility in Medicine and Research (PRIM&R)
Mission: Public Responsibility in Medicine and Research (PRIM&R) is dedicated to advancing the highest ethical standards in the conduct of research through education, membership services, professional certification, and public policy initiatives. Via a wide variety of conferences and courses, PRIM&R provides balanced, well-researched, and accurate information on the range of ethical and regulatory issues affecting research while also offering unparalleled access to certification, networking, and professional development resources. For more information visit the PRIM&R website at www.primr.org .
PRIM&R is the professional home for those whose responsibilities include the protection and welfare of human and animal subjects. PRIM&R strives to enhance the ethical and responsible conduct of research through the educational and professional development of its members. Members include professionals from around the world responsible for overseeing the use of human and animal research subjects, including administrators, government officials, and academic department chairs, as well as members of institutional review boards, human research protection programs, animal care and use committees, and institutional biosafety committees.
PRIM&R sponsors two certification initiatives; the Certification for IRB Professionals (CIP®), for individuals working with institutional review boards and human research protection programs, and the Certification for Professional IACUC Administrators (CPIA), for those working with animal care and use committees. These credentials strengthen each profession by providing established bodies of relevant knowledge and standards of practice, and by providing potential career advancement opportunities.
Society of Clinical Research Professionals (SoCRA)
The Society of Clinical Research Associates, a professional membership organization, was developed to provide educational programs, certification, and a forum for research professionals to exchange information.
SoCRA established the Certification Program for Clinical Research Professionals (CCRPs) in order to create an internationally accepted level of knowledge, education, and experience by which clinical research professionals will be recognized by the medical research community.
A Clinical Research Professional may serve as a clinical investigator, sub-investigator, clinical researcher, research nurse, administrator, coordinator, data manager, project manager, IRB coordinator, Quality Assurance specialist, regulatory affairs specialist, research pharmacist, consultant, or educator in clinical trials management. The examination is based on those areas that are common to all Clinical Research Professionals; any member of the clinical research team is able to apply for this certification. Questions are formulated to be straight -forward and easily understood. For more information visit the SoCRA website at www.socra.org.
Society of Research Administrators (SRA) International
Mission: To globally foster and strengthen research management, administration and knowledge transfer in research management and administration.
The Society of Research Administrators International maintains 12 certificate programs encompassing every aspect of Research Administration – Hospitals, Universities, Nonprofits and Commercial Institutions. SRA’s certificate programs offer comprehensive training specific to today’s educational needs of research administrators.
The curriculum for each program includes a required half-day or full-day workshop, and four (4) to eight (8) required sessions, which are held at various SRA meetings throughout the year.
SRA’s 12 Certificate Programs are:
Clinical Trials Research Administration 101
Clinical Trials Research Administration 201
Human Research Protections
Introduction to Research Administration and Management
National Institutes of Health Grants Fundamentals
The Practice of Research Administration and Management
For more information visit the SRA website at www.srainternational.org
Office of Research Compliance – Case Western Reserve University
For more information about:
- The Belmont Report
- WMA Declaration of Helsinki
- University Hospitals Institutional Review Board Policies and Procedures
- FDA Regulations Relating to Good Clinical Practice and Clinical Trials
- FDA Information Sheets for IRBs and Investigators
- Office for Human Research Protections
- Office of Research Integrity
- FDA ICH E6: Good Clinical Practice: Consolidated Guidance (PDF)
- Department of Health and Human Services – Regulations