Clinical Research Guidebook

Penn State University conducts research studies according to FDA regulations and International Conference of Harmonization (ICH) guidelines. International Conference on Harmonization Guideline for Good Clinical Practice (GCP), as described by the FDA, is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety, and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible. The FDA states that the guideline should be followed when generating clinical trial data that are intended to be submitted to regulatory authorities. 

There are multiple research administration support offices available at University Park that can help with different aspects of conducting clinical trials.

• Office of Technology Management
• Penn State Clinical and Translational Science Institute
• Human Research Protection Program (HRPP) 
• Office of Sponsored Programs
• Office for Research Protections Quality Assurance Program

For more clinical trial resources visit the ORP clinical trials webpage or email qm-orp@psu.edu.

This guidebook is intended for investigators affiliated with University Park colleges or commonwealth campuses and provides up-to-date information about requirements and regulations for clinical research. Reference this website, not printouts, for the most recent information.

The College of Medicine has a comparable guidebook specific to its faculty, staff, and students.

The Penn State IRB Investigator Manual (HRP-103) is designed to guide you through policies and procedures related to the conduct of Human Research that are specific to this institution. General information regarding Human Research protections and relevant federal regulations and guidance is incorporated into the required human protections training.

It is recommended that all study team members review the Investigator Manual and become familiar with its contents. The manual is updated regularly and can serve as an initial source of information when questions arise regarding policies and procedures.

The IRB Investigator Manual is available in the CATS IRB Library and can also be found in the ORP Website. 

Penn State has a number of policies relevant to clinical research. Research protections policies include:

• RP03 The Use of Human Participants in Research
• RP05 Research Quality in Human Participant Research
• RP07 HIPAA and Research at Penn State University
• RP11 Use of Regulated and Biohazardous Materials in Research and Instruction 

Important research administration policies include:

• RA03 Eligibility to Serve as Principal Investigator (PI)
• RA04 Gifts, Grants and Contracts (The Funding Matrix)
• RA20 Proposal Submission
• RA21 Development of Proposal Budget
• RA80 Subawards and Subcontracts
• RA90 Finalization and Closure

To browse all Universities policies, including others that might be relevant to a particular clinical research project, please visit the Penn State Policies website.

Some studies defined as "clinical research" or a "clinical trial" have special compliance requirements. For compliance purposes, there are three definitions of clinical trials depending on the funding or regulatory oversight. Studies with NIH funding follow the Common Rule definition, which is a similar definition used by other federal funding agencies. FDA-regulated research defines a clinical trial as research meeting the criteria of an "applicable clinical trials" (ACT). Visit the Quality Assurance webpage on clinical trials to learn more. 

The U.S. Department of Health and Human Services (HHS) is the government’s principal agency for protecting the health of all Americans. It comprises several public health services agencies including the FDA (Food and Drug Administration), OHRP (Office of Human Research Protection), the NIH (National Institutes of Health), and the Centers for Medicare and Medicaid Services (CMS).

Food and Drug Administration is responsible for protecting and promoting public health through the regulations and supervision of food safety, tobacco products, dietary supplements, prescription and over-the-counter pharmaceutical drugs (medications), vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices (ERED), veterinary products, and cosmetics. Understanding these rules is critical for any investigator who conducts human subject studies with drugs, devices or dietary supplements, whether already approved on the market, or still investigational.

Office of Human Research Protection provides leadership, guidance, and education in the protection of the rights, welfare, and well-being of subjects involved in research conducted or supported by the HHS. OHRP performs these services through providing clarification and guidance, developing educational programs and materials, maintaining regulatory oversight, and providing advice on ethical and regulatory issues in biomedical and social-behavioral research. Detailed regulations for human subject protection are listed on the OHRP website. OHRP rules guide the Institutional Review Boards (IRBs).

National Institutes of Health seeks to provide fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce the burdens of illness and disability. As part of this mission NIH provides leadership and direction to programs designed to improve health and provides support for research. As of December 2017 2017, the NIH funds 57 Clinical and Translational Science Centers across the country. Working together as a national consortium, Clinical Translational Science Award (CTSA) institutions share a common vision to improve human health by transforming the research and training environment to enhance the efficiency and quality of clinical and translational research. The CTSA program is supported by the National Center for Advancing Translational Science (NCATS), part of the National Institutes of Health. The CTSA program has the following overriding objectives:

• Provide a comprehensive array of essential tools and services to spark clinical and translational research.
• Ensure the training of a well-prepared workforce of trainees, staff, and investigators.
• Effectively communicate the many tools, services, and training opportunities to ensure innovative translational science advances that will improve human health.

Today, Penn State Clinical and Translational Science Institute offers resources that faculty, trainees and staff across the scientific and medical spectrum can use to enhance research and improve health and healthcare delivery.

Centers for Medicare and Medicaid Services is the federal agency which administers Medicare, Medicaid, and the Children’s Health Insurance Program. At this time, CMS requirements are only applicable at the College of Medicine.

The Code of Federal Regulations is a compendium of the general and permanent rules and regulations published in the Federal Register by the federal executive departments and agencies. The CFR is divided into 50 titles that represent broad areas subject to Federal regulations. Title 45 CFR encompasses regulation of Public Welfare. Title 21 CFR is administered by the FDA and covers regulations of Food and Drugs. Title 45 CFR 46 (The Common Rule) is a core set of regulations defining protection of Human Subjects in clinical research. 45 CFR part 46 includes four subparts:

• Subpart A, also known as the Federal Policy or the “Common Rule”
• Subpart B, additional protections for pregnant women, human fetuses and neonates
• Subpart C, additional protections for prisoners
• Subpart D, additional protections for children

Through a system of IRB registration and assurances, HHS regulations require institutions to commit to compliance with 45 CFR 46 before initiating participation in HHS-conducted or -supported research involving human subjects. The main elements of the Common Rule include: What human research issues are addressed in 45 CFR part 46? HHS regulations at 45 CFR part 46 stipulate substantive and procedural requirements for investigators and institutions engaged in HHS-supported or -conducted research. Specifically, in addition to providing definitions and information about application of the regulations, specific sections of the regulations address the following topics:

• Assuring compliance with the regulations (46.103)
• Institutional Review Board (IRB) membership (46.107)
• IRB functions and operations (46.108)
• IRB review of research (46.109)
• Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research (46.110)
• Criteria for IRB approval of research, including minimizing risk, ensuring confidentiality, and protecting vulnerable populations, (46.111)
• Review by institution (46.112)
• Suspension or termination of IRB approval of research (46.113)
• Cooperative research (46.114)
• IRB records (46.115)
• General requirements for informed consent (46.116)
• Documentation of informed consent (46.117)
• Applications and proposals lacking definite plans for involvement of human subjects (46.118)
• Research undertaken without the intention of involving human subjects (46.119)
• Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency (46.120)
• Use of Federal funds (46.122)
• Early termination of research support: Evaluation of applications and proposals (46.123)
• Conditions (46.124)

Additional protections for specific populations have been adopted by HHS (and other departments and agencies to a lesser extent), as follows:

• Subpart B, Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research
• Subpart C, Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects
• Subpart D, Additional Protections for Children Involved as Subjects in Research

Since 1991, 45 CFR 46 was formally adopted by more than a dozen other Departments and Agencies that conduct or fund research involving human subjects. The Department of Veterans Affairs promulgated this same rule at 38 CFR 16. Today, this Federal Policy is shared by 17 Departments and Agencies, representing most, but not all, of the federal Departments and Agencies sponsoring human-subjects research.

Title 21 CFR: The FDA regulations (Title 21 CFRs) are applicable when research is being conducted to develop a medical product that will be licensed for sale in the United States. Certain federally sponsored and privately sponsored research is subject to the regulations of the FDA according to 21 CFR 50 and 56. Title 21 CFR 50 defines regulations for informed consent and 21 CFR 56 defines regulations for IRBs. These regulations largely overlap but are not identical with the Common Rule. Investigators need to know both sets of regulations to apply them appropriately. Title 21 CFR 312 details the regulations for human research done with investigational drugs. This Title includes, but is not limited to, the regulations for applying to FDA to conduct research under an Investigational New Drug (IND) application (21 CFR 312 Subpart B), responsibilities of Sponsors and Investigators under an IND (21 CFR 312 Subpart D), and expanded access to Investigational Drugs (21 CFR 312 Subpart I). The IND and IDE Submissions section of this guidebook discusses the drug development process in more detail. Title 21 CFR 812 details the regulations for human research with investigational devices. The regulations lay out the framework for applying to FDA to conduct human subjects research with Investigational Devices (21 CFR 812 Subpart B), responsibilities of Sponsors (21 CFR 812 Subpart C) and Investigators (21 CFR 812 Subpart E), and IRB approval 21 CFR 812 Subpart D). The IND and IDE Submissions section of this guidebook discusses the drug development process in more detail.

Penn State has approved Federal Wide Assurances with the Department of Health & Human Services. Penn State's two IRBs are also registered with the Department of Health & Human Services.

• University Park and all campus locations:  FWA00001534
• College of Medicine and Penn State Health:  FWA00004251

The expiration date for this assurance changes frequently. If you need the expiration date, please visit http://ohrp.cit.nih.gov/search/asurfnd.asp, enter the FWA Number above, and click “Search. 

IRBs for all Campuses:

• IORG#0000031
• Registration Number for IRB #1:  IRB00000046
• Registration Number for IRB #2:  IRB00000047

Penn State uses the Collaborative Institutional Training Initiative (CITI) program to offer content that fulfills that human subjects research training requirement for IRB approval. The CITI human subjects training includes a required module on HIPAA privacy and security that fulfills HIPAA training for investigators human subjects research. Click here to begin training in CITI.

The NIH requires that all study team members working on NIH-funded clinical trials complete good clinical practice training, and the CITI course fulfills the requirement. The CITI course conforms to the International Conference on Harmonization Guideline for Good Clinical Practice (ICH GCP).

Other IRB Trainings

During the academic year, the Penn State Office for Research Protections (ORP) hosts a number of workshops on human subjects research and research ethics. View upcoming workshops or request a workshop for your group.

The ORP also provides in-person and live virtual training that includes instructions for how to prepare a submission to the IRB. Find upcoming trainings on the ORP Education page under trainings. See upcoming ORP trainings and workshops.

Biohazardous materials include human biological specimens, infectious agents, recombinant material, and gene therapy. Biological toxins and carcinogens are also included if they are used in conjunction with animals. The following trainings are required before investigators can be given approval to ship biohazardous materials or use them in teaching or research. The following CITI trainings are required dependent on the nature and use of the materials and must be taken yearly:

• Transporting Dangerous Goods: Shipping Biohazardous Biological Material Training
• Working with biohazardous material, regulated materials, infectious agents, and recombinant DNA: Yearly BioSafety Training
• Working with human blood, blood products, human body fluid, human tissue and/or cell lines: OSHA Bloodborne Pathogens Training
• Dual Use Research of Concern (DURC): Dual Use Research of Concern (DURC) Training

To learn more about Biohazardous Materials Training go to the IBC Training page.

All investigators who are engaged in research must complete Penn State University’s required Financial Conflict of Interest (FCOI) training and submit a disclosure of significant financial interest. Per PSU policy RP06 Disclosure and Management of Significant Financial Interests, an investigator is defined as “any individual, regardless of his or her title or position, whether faculty, staff, or student, who has the ability to make independent decisions related to the design, conduct or reporting of University Research, but not including individuals who perform only incidental or isolated tasks related to a University Research project.”

Both FCOI training and disclosure are completed via Penn State University’s electronic Conflict of Interest System, COINS. As part of the electronic Disclosure Form, COINS requires investigators to complete FCOI training upon their first disclosure and again every four years. For details, please see the the Office for Research Protections Conflict of Interest website.

Penn State has developed an Electronic Regulatory Binder (eReg Binder) that can be uploaded to Research Electronic Data Capture (REDCap) as a project that investigators can use to stay in compliance with documentation requirements for good clinical practice and federal regulations. The eReg Binder is an online "filing cabinet" for all study documents and conforms to the ICH GCP guideline. Read more about the eReg Binder. 

Access to REDCap requires an account and some training. Learn more about REDCap on the CTSI website.

The Office of Sponsored Programs (OSP) oversees the proposal submission process and negotiates contractual terms and conditions of awards, with the goal of promoting, fostering and sustaining excellence in basic and clinical research.

Principal Investigators do not have the authority to submit proposals on their own. Investigators should contact their college or unit research administrators as soon as they learn of a funding opportunity. Learn more on about internal approval process at Penn State on OSP's website.

The Penn State Research Portal (PURE) is a publicly-available system that captures and displays the research output of the University, both for investigators and units, and facilitates collaboration between investigators across the University and beyond. Pure aggregates research information from internal and external sources and enhances the visibility and discoverability of research at Penn State, both internally and externally. It provides detailed information on scholarly output, publications, networks, citation data from journals and social media citations. 

The Penn State Clinical and Translational Science Institute (CTSI) can provide a wide range of consultation services during all stages of studies, and specifically during the project development and start-up phases. See CTSI consultation services:

• Biostatistics, Epidemiology and Research Design
• Communication
• Community Engagement
• Health Policy Impact
• Informatics
• Recruitment and Retention
• Regulatory
• Research Ethics
• Teams and Collaboration

The Clinical Research Center (CRC) provides clinical research expertise, facilities and resources to Penn State investigators. Resources include unique facilities and equipment, as well as highly experienced staff who are trained in human subjects’ protection, good clinical practices, protocol implementation and compliance. The facilities at University Park CRC are approximately 6,800 square feet and include five patient exam rooms, an interview/consult room, a DXA room, two procedure rooms, three infusion sleep rooms and an exercise room. Support areas include: the reception and waiting area, a secure file room, a nursing station, a small patient nutrition area, specimen processing and computer support area. In addition, the CRC has a staff dietitian and a metabolic kitchen for specialized nutrition services for research studies. The CRC provides outpatient rooms, nurses, physicians and nurse practitioners experienced in conducting clinical trials, and general supplies and equipment necessary to perform quality clinical research studies. The highly skilled clinical research nurses implement protocol- specific procedures and provide direct nursing care for all subjects enrolled in research studies. CRC nurses are committed to subject safety and protocol fidelity and are certified in ACLS.

REDCap (Research Electronic Data Capture) is a secure web application for building and managing online surveys and research databases. It is a novel workflow methodology and software solution designed by Vanderbilt University for rapid development and deployment of electronic data capture tools to support clinical and translational research. Using REDCap’s streamlined process for rapidly developing projects, you may create and design projects using

• The online method from your web browser using the Online Designer
• The offline method by constructing a “data dictionary” template file in Microsoft Excel, which can be later uploaded into REDCap.

Both surveys and databases (or a mixture of the two) can be built using these methods. REDCap provides audit trails for tracking data manipulation and user activity, as well as automated export procedures for seamless data downloads to Excel, PDF, and common statistical packages (SPSS, SAS, Stata, R). Also included are a built-in project calendar, a scheduling module, ad hoc reporting tools, and advanced features, such as branching logic, file uploading, and calculated fields. REDCap has a quick and easy software installation process, so that you can get REDCap running and fully functional in a matter of minutes. Technical support is available for users of REDCap.

A user account with some training is required. Learn more about REDCap on the CTSI website.

The Trial Innovation Network is a new collaborative initiative within the CTSA Program and is composed of three key organizational partners – the CTSA Program Hub network, the Trial Innovation Centers (TICs), and the Recruitment Innovation Center (RIC). All are key partners of the Trial Innovation Network and make unique and essential contributions. Other important partners include NIH Institutes, other federal and non-federal stakeholders, researchers, patients, providers, and the public. The local Penn State Hub Liaison Team works together to provide support and resources for investigators to develop proposals into protocols, optimize study operations, and enhance recruitment and enrollment. Investigators must contact their local Trial Innovation Liaison Team to discuss their proposal and obtain a brief consultation prior to submission. A consultation with the local Trial Innovation Liaison Team is important because these teams will directly connect the local hubs to the national network and provide advice and input on proposals. Learn more on the CTSI website and the Trial Innovation Network national site.

ACT Network

The Accrual to Clinical Trials (ACT) Network is a real-time platform for researchers to explore and validate the feasibility for clinical studies across the NCATS Clinical and Translational Science Award consortium. ACT helps researchers design and complete clinical studies and is secure, HIPAA-compliant and IRB-approved.

With the ACT Network, researchers can:

• Explore patient populations: Learn about a patient population in-depth and in real-time from their computer.
• Check the feasibility of clinical studies: Iteratively test and refine inclusion and exclusion criteria to confirm the feasibility of a clinical study.
• Find partner sites: Search for patients across the CTSA network to identify potential partners for multi-site studies.
• Demonstrate feasibility: Access easy-to-download results for use in funding proposals and IRB submissions to demonstrate the feasibility of a clinical study.

Learn more about the ACT Network on the CTSI website.

 

i2b2

A pool of potential study subjects can be estimated using i2b2. i2b2 (Informatics for Integrating Biology and the Bedside) is an NIH-funded National Center for Biomedical Computing based at Partners HealthCare System. The i2b2 Center is developing a scalable informatics framework that will enable clinical researchers to use existing clinical data for discovery research and, when combined with IRB-approved genomic data, facilitate the design of targeted therapies for individual patients with diseases having genetic origins. This platform currently enjoys wide international adoption by the CTSA network, academic health centers, and industry. i2b2 is funded as a cooperative agreement with the National Institutes of Health. Learn more about i2b2 on the CTSI website.

Because it may be necessary for a researcher to obtain access to and review PHI in order to prepare a research study, HIPAA rules allow such a review upon compliance with specified criteria. An application for review of PHI preparatory to research must be submitted to the IRB for review and approval.

For researchers at UP and all other campuses and colleges, the “Data Collection for Reviews Preparatory to Research” form located on the IRB website should be submitted as a supporting document in the CATS IRB submission. In most cases, investigators conducting chart reviews to prepare a study should use the protocol template HRP-596 – Protocol for Human Subject Research - Chart Review and/or Analysis of Existing Restricted Data Set Study for their submission. The template can be found in the CATS IRB “Library.”

For additional information see Penn State policy RP07 HIPAA and Research at Penn State University.

This activity is required for industry-sponsored clinical studies and investigator-initiated clinical studies with funding from industry and may be needed for other research activities. In many instances a sponsor sends a Confidential Disclosure Agreement (CDA) prior to sharing a protocol or confidential documents. PIs should contact the Office of Sponsored Programs for more information and assistance.

College or unit administrators assist investigators submit applications and develop their non-technical sections, including the budget.

The CTSI provides provides proposal development services. Learn more and access the consultation form on the CTSI website.

The Strategic Interdisciplinary Research Office (SIRO) is a research administration unit of the Office of the Vice President for Research that supports both the development of proposals and the administration of large and strategic projects at Penn State. A typical SIRO project is over $1,000,000 per year and involves:

• Faculty from more than three PSU colleges, campuses or institutes
• Many large subcontracts, especially international
• Extensive institutional data sets (e.g. training grants)
• Major shared resources
• Detailed extra sections (e.g. consortium, team or data management plans; outreach plans; formal evaluation or assessment; GANTT charts)
• International collaboration/engagement

Visit the SIRO website to learn more about SIRO’s services.

The CTSI BERD (Biostatistics, Epidemiology and Research Design) Core consultations pool Penn State resources across campuses to offer training in biostatistical and epidemiological methodologies and assistance to investigators in study design, data management and analysis. BERD provides for free up to four hours of consultation per project for the development of clinical and translational science external grant proposals and consultations for institute-funded pilot projects. Visit the CTSI Consultations website to learn more about BERD consultations and upcoming BERD seminars.

The Statistical Consulting Center (SCC) provides statistical advice and support to Penn State researchers and external clients in industry and government. The SCC provides support in the following areas:

• Research Planning
• Design of Experiments and Survey Sampling
• Statistical Modeling and Analysis
• Analysis Results Interpretation
• Advice on appropriate software for data analysis

Visit the Statistical Consulting Center website to learn more about their services.

Monitoring is the act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCPs), and the applicable regulatory requirement(s). Typically, academic sites are familiar with monitors assigned by a sponsor or a contract research organization (CRO). However, GCP requires that investigator-initiated trials enrolling human subjects also provide a monitoring plan to assure that the data collected throughout the study are accurate. In addition, the Code of Federal Regulations requires monitoring under 21 CFR 312 subpart D (for INDs) and 21 CFR 812 subpart C (for IDEs). Sponsors (including Sponsor-Investigators) of clinical investigations conducted under an IND or IDE are required to provide oversight to ensure adequate protection of the rights, welfare, and safety of human subjects and the quality and integrity of the resulting data submitted to FDA. This oversight is maintained through the regular review of the source data, case report forms, informed consents, regulatory documents, and any other essential documents by a monitor. During a monitoring visit, a monitor reviews individual subject records and source documents, regulatory binder(s), and other essential documents and compares the information with data recorded on the case report forms (CRF) or entered in the electronic case report form (eCRF). The monitor is obligated to ensure the following:

• Subjects meet eligibility requirements
• The rights and safety of human subjects are protected
• Informed consent has been obtained and documented appropriately
• Conduct of trial is in compliance with protocol, good clinical practice (GCP), and applicable regulatory requirements Subject was followed and treated according to the protocol
• Reported trial data are accurate, complete, and 100% verifiable from source documents; all pertinent information in the subject records must be accurately recorded on the CRF
• The CRF is complete, legible, and consistent throughout visits

Typically, in an industry-sponsored study, the pharmaceutical company will provide the monitor for the study. However, in the case of a study conducted by a Sponsor-Investigator, the Investigator takes on the responsibility of ensuring that the study is being monitored. For industry-sponsored studies a monitoring plan will often be used to guide the frequency of monitoring visits to investigative sites whereas in an Investigator-initiated study the Investigator and/or study staff should develop a monitoring plan. The frequency of visits is affected by the complexity of the study and the rate of enrollment. Monitoring plans can be updated during the course of the study if, for example, enrollment is faster than expected. When a monitor comes to a clinical site to conduct a monitoring visit, he/she will need access to all source documents.

Data and Safety Monitoring Boards (DSMBs) and Data and Safety Monitoring Committees (DSMCs) carry out important aspects of clinical trial monitoring. A clinical trial Data Monitoring Committee is a group of individuals with pertinent expertise that reviews on a regular basis accumulating data from one or more ongoing clinical trials. The DSMB advises the investigator regarding the continuing safety of trial subjects and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of the trial. DSMBs have the practical position of seeing data and safety information in more frequent intervals and with typically more statistical expertise to make enhanced assessments about a study’s progress and determine the study’s future.

To learn more about DSMBs, please see the information provided by the College of Medicine.

FDA’s Center for Drug Evaluation and Research (CDER) is responsible for regulating manufacturing, testing and importation of pharmaceutical drugs in the US. This includes new drug approvals, abbreviated new drug approvals (generics), over-the-counter drugs, animal drugs and biologics. A drug is defined as:

• A substance intended for use in diagnosis, cure, mitigation, treatment, or prevention of the disease;
• Substances (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 component of a device.

An IND is a request for FDA authorization to administer an investigational drug or biological product to humans. The application must show results of preclinical experiments, if applicable; the chemical structure of the compound; how it is thought to work in the body; any side effects found in animal studies; and how the compound is manufactured (chemistry, manufacturing and controls section). The IND must also include a detailed clinical trial plan, including how, where and by whom the studies will be conducted. Based on the information of the IND application, the FDA will determine if there is sufficient evidence to support initial human testing. The sponsor must wait 30 days after submitting the IND to the FDA for review. At the end of the 30 day review period, unless the FDA identifies a potential safety problem involving the use of the drug and asks for a delay, the sponsor may begin the proposed clinical testing.

The Office for Research Protections Quality Assurance Program can help investigators apply for an IND. Contact them at orp-qm@psu.edu.

Preclinical testing begins after a potential drug has been identified in the lab. Preclinical testing involves lab and animal studies that evaluate the drug’s toxic and pharmacologic effects. Preclinical studies are also subject to the FDA regulations known as Good Laboratory Practices (GLP) for Nonclinical Laboratory Studies, 21 CFR 58. The GLP regulations specify minimum standards in such areas as personnel, facilities, equipment and operations.

Preclinical testing includes pharmacokinetics, the study of how the drug moves through living organisms. Researchers examine absorption, distribution, metabolism and excretion (also abbreviated as ADME) to ensure that the drug reaches its intended target and passes through the body properly. In addition to the biological tests, researchers conduct chemistry tests to establish the drug’s purity, stability and shelf life. Manufacturing tests are conducted to determine the feasibility of producing the drug on a large scale and to explore dosing, packaging and formulation (e.g., pill, inhaler, injection). At the preclinical stage, the FDA will generally ask, at a minimum, that sponsors:

• develop a pharmacological profile of the drug;
• determine the acute toxicity of the drug in at least two species of animals, and
• conduct short-term toxicity studies ranging from two weeks to three months, depending on the proposed duration of use of the substance in the proposed clinical studies.

FDA Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products

After clinical trials have been completed demonstrating safety and effectiveness, the study sponsor (or drug manufacturer) will submit a New Drug Application (NDA) to the FDA for a license to market the drug for a specified indication. NDAs contain all of the information about all of the studies, including preclinical testing, all clinical trials, dosing information, manufacturing details and proposed labeling for the new medicine. Most academic drug development efforts do not progress to this stage. At NDA submission stage, FDA scientists review all the results from all the studies carried out over the years and determine if they show that the medicine is safe and effective enough to be approved. During this review, the FDA determines what the labeling should be and whether the sponsor can manufacture it properly and consistently. Once the drug is approved, it becomes available for physicians to prescribe for the indication approved by the FDA. The review process takes approximately 18 months.

Many academic investigators will want to conduct a clinical study with an already approved drug. This is often done to establish efficacy in a new disease indication. FDA provides provisions for conducting studies of lawfully marketed drugs through the use of an IND exemption. A clinical investigation of a drug is exempt from the IND requirements if all of the criteria for an exemption in 21 CFR 312.2(b) are met:

• The drug product is lawfully marketed in the United States;
• The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication and there is no intent to use it to support any other significant change in the labeling of the drug;
• The investigation is not intended to support a significant change in advertising to an existing lawfully marketed prescription drug product;
• The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product;
• The investigation will be conducted in compliance with the requirements for institutional review set forth in FDA regulations 21 CFR 56, and requirements for informed consent as set forth in FDA regulations 21 CFR 50;
• The investigation will be conducted in compliance with FDA regulations 21 CFR 312.7: Promotion of investigational drugs.

FDA Guidance: Investigational New Drug Applications (INDs) – Determining whether Human Research Studies can be conducted without an IND.

The Office for Research Protections Quality Assurance Program can help investigators determine whether or not an IND is needed. Contact them at orp-qm@psu.edu.

Investigator means an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. “Sub-investigator” includes any other individual member of that team (21 CFR 321.3).

Sponsor means a person who takes responsibility for and initiates a clinical investigation (21 CFR 312.3). The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator.

Sponsor-Investigator means an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed (21 CFR 312.3). The term does not include any person other than an individual. If an academic investigator submits an IND or IDE or obtains an abbreviated IDE from the IRB and is the principal investigator, the investigator is the Sponsor-Investigator and he/she is responsible for regulatory compliance. Academic investigators sometimes equate the term “Sponsor” with the source of the study funding. In fact, there are two types of sponsors: regulatory sponsor and financial sponsor. The regulatory sponsor is the person/entity who initiates and takes responsibility for a clinical investigation. The regulatory sponsor submits the IND or IDE when applicable and is responsible for communications with the FDA. The regulatory sponsor may be a pharmaceutical company, a private or academic organization, or an individual. A financial sponsor may be a company, a department, a non-profit or a government agency. If a pharmaceutical (or device) company is supplying a drug (or device) for an academic study, but will not be submitting the IND or IDE, the company is not the regulatory sponsor. For commercial INDs, the financial and regulatory sponsors are usually the same (i.e. the pharmaceutical or device company).

Many clinical studies of academic investigators evaluate the effect of foods or dietary supplements on the disease or physiological parameters. Some of these studies may require an IND submission. If the foods or dietary supplements are investigated for diagnosis, cure, mitigation, treatment, or prevention of disease and are used to affect the structure or function of the body, then the food or dietary supplement will be considered a drug for the purposes of this study. The study will be the subject to the same regulations as any other unapproved drug.

Penn State’s IRB relies on written communication from the FDA with regard to the use of foods and dietary supplements to determine the need for an IND. According to IRB policy, Penn State investigators are required to contact the FDA to obtain written communication from the FDA documenting the IND number or stating that an IND is not required for any human research study evaluating a food or dietary supplement, with limited exceptions. Exceptions to this policy generally include the following; 1) taste and food quality evaluations and consumer acceptance studies which qualify as exempt from IRB review or 2) studies in which the use of a food or dietary supplement would qualify as exempt from IRB review if not combined with other procedures that do not qualify as exempt from IRB review (i.e. must be reviewed at expedited or committee level). This written communication from the FDA must be provided to the IRB with the CATS IRB submission. For more on IRB policy, see the IRB Investigator Manual.

Sponsor-Investigator responsibilities under an IND or IDE are covered in 21 CFR 312 (for drugs) and 21 CFR 812 (for devices). FDA Guidance: Investigator Responsibilities – Protecting the Rights, Safety and Welfare of Study Subjects.

The Office for Research Protections Quality Assurance Program is available to assist with IND preparation, submission, and maintenance. Contact them at orp-qm@psu.edu.

For guidance and templates for your IND application, see the Quality Assurance Program’s resources.

FDA’s Center for Devices and Radiological Health (CDRH) is responsible for regulating manufacturing and importation of medical devices sold in the United States. In addition, CDRH regulates radiation-emitting electronic products (medical and non-medical) such as lasers, X-ray systems, ultrasound equipment, microwave ovens and color televisions. If a product is labeled, promoted or used in a manner that meets the definition in section 201(h) of the Federal Food Drug & Cosmetic (FD&C) Act, it will be regulated as a medical device. A device is an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:

• Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals;
• Or intended to affect the structure or any function of the body of man or other animals:
• And does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.

This definition provides a clear distinction between a medical device and other FDA regulated products such as drugs. If the primary intended use of the product is achieved through chemical action or by being metabolized by the body, the product is usually a drug. FDA Guidance: Frequently Asked Questions about Medical Devices

The Office for Research Protections Quality Assurance Program can help investigators determine if their research involves testing a FDA-regulated medical device. Contact them at orp-qm@psu.edu.

The FDA has established classifications for approximately 1,700 different generic types of devices and grouped them into 16 medical specialties referred to as panels. Each of these generic types of devices is assigned to one of three regulatory classes (Class I, Class II and Class III) based on the level of control necessary to assure the safety and effectiveness of the device. The device classification defines the regulatory requirements for an approval of a new device. Regulatory control increases from Class I to Class II to Class III. Device classification depends on the intended use of the device and also upon indications for use. In addition, classification is risk based, that is, the risk the device poses to the patient and/or the user is a major factor in the class it is assigned.

Examples:

Class I devices: elastic bandages, examination gloves, and hand-held surgical instruments.

Class II devices: powered wheelchairs, infusion pumps, and surgical drapes.

Class III devices: implantable pacemaker pulse generators and coronary stents.

To find the classification of a device, as well as whether any exemptions may exist, the classification regulation number should be determined for the device. One of the ways to accomplish this is to go directly to the FDA classification database and search for a part of the device name. Once the correct classification regulation has been identified, go to the device panel (medical specialty) to which the device belongs. The search will provide the Device Classification and the appropriate CFR regulation for the device. If the device is not classified, similar devices can be researched on the FDA website (PMA and 510(k) databases) or pre-IDE consultation can be used for the FDA determination.

The Office for Research Protections Quality Assurance Program can help investigators determine if their research involves testing a FDA-regulated medical device. Contact them at orp-qm@psu.edu.

Devices used on human subjects to conduct investigations of safety and effectiveness are considered “Investigational Devices” (Section 520(g) of FD&C Act). Significant Risk (SR) device presents a potential for serious risk to the health, safety and welfare of a subject, and

Intended to be used as an implant;

• Or purported to support or sustain human life;
• Or is used for substantial importance in diagnosing, curing, mitigating or treating disease;
• Or otherwise presents a potential for serious risk to the health, safety, or welfare of a subject

Examples of SR devices include sutures, cardiac pacemakers, hydrocephalus shunts, and orthopedic implants. Conversely, non-significant risk (NSR) device studies do not pose a significant risk to patients. Non-significant risk should not be confused with “minimal risk,” a term used by the FDA to classify studies. Examples of NSR devices include most day-wear contact lenses and lens solutions, ultrasonic dental scalers, and foley catheters. SR devices must meet all regulatory requirements set in 21 CFR 812, including the requirement for approval by both IRB and the FDA before commencing the study. Significant risk devices require submission of an investigational device exemption (IDE) to CDRH. NSR device studies may commence without FDA approval, based solely on the IRB approval. However, the sponsor-investigator must follow abbreviated IDE requirements, which are, in essence, the same requirements as regular IDE only without FDA submission (21 CFR 812.2 (b)). The IRB acts as a surrogate overseer for the FDA.

FDA Guidance: Significant Risk and Non-significant Risk Medical Device Studies

The Office for Research Protections Quality Assurance Program can help investigators determine if a device is SR or NSR. Contact them at orp-qm@psu.edu.

Important: Clinical study of a new indication or new patient population for an already marketed device falls under the IDE regulations. Per Penn State University Policy RP05, “Research Quality in Human Participant Research,” it is required that the Office for Research Protections Quality Management Program be contacted to provide support for the submission process for IDEs or Study Risk Determinations, and to perform an administrative review of the submission prior to being sent to the FDA. An investigational device exemption (IDE) is a regulatory submission to the Center for Devices and Radiological Health (CDRH). If approved, it allows the investigational device to be used in a clinical study in order to collect safety and effectiveness data. IDE requirements:

• Study approved by an 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 obtained and documented;
• The device is labeled “CAUTION- Investigational Device. Limited to investigational use only;” Sponsor-investigator complies with monitoring requirements;
• Records and reports are maintained;
• Investigator cannot promote or commercialize (charge for) the device.

FDA Guidance: Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies Two important elements of the guidance are:

• FDA approval of an IDE application for an early feasibility study, including some first-in-human studies, may be based on less nonclinical data than would be expected for other types of studies (e.g., traditional feasibility or pivotal).
• The introduction of new approaches to facilitate timely device and clinical protocol modifications during an early feasibility study, while still maintaining compliance with the IDE regulations in 21 CFR 812: more types of modifications that can be made under a 5-day notification without prior FDA approval, as compared with other types of studies; a contingent approval process that permits changes contingent upon acceptable; nonclinical test results without requiring additional FDA action; and interactive review of IDE supplements and amendments.

Studies of non-significant risk devices are subject to abbreviated IDE requirements. An IDE submission to the FDA is not required under the abbreviated requirements, but the requirements for labeling, IRB approval, informed consent, monitoring, records, reports and promotional practices contained in FDA regulations still apply (21 CFR 812.2(b)).

Requirements under abbreviated IDE:

• The sponsor will label the device in accordance with 21 CFR 812.5.
• The sponsor will obtain and maintain IRB approval throughout the investigation as a nonsignificant risk device.
• The sponsor will ensure that each investigator participating in an investigation of the device obtains and documents consent from each subject under the investigator’s care according to 21 CFR 50, unless documentation is waived by an IRB.
• The sponsor will comply with the requirements of 21 CFR 812.46 with respect to monitoring investigations.
• The sponsor will maintain the records required under 21 CFR 812.140(b) (4) and (5) and make the reports required under 21 CFR 812.150(b) (1) – (3) and (5) – (10); The sponsor will ensure that participating investigators will maintain the records required by 21 CFR 812.140(a)(3)(i) and make the reports required under 812.150(a) (1), (2), (5), and (7).
• The sponsor will comply with the prohibitions in 21 CFR 812.7 against promotion and other practices.

Some studies may be exempt from the IDE regulations. The exemption criteria is explained in 21 CFR 812.2(c), and briefly summarized here:

• A legally marketed device when used in accordance with its labeling;
• A diagnostic device, if it is
  • noninvasive;
  • does not require an invasive sampling procedure that presents significant risk;
  • does not by design or intention introduce energy into a subject;
  • and is not used as a diagnostic procedure without confirmation of the diagnosis by another medically established diagnostic product or procedure.
• Consumer preference testing, testing of a modification, or testing of a combination of two or more devices in commercial distribution, if the testing is not for the purpose of determining safety or effectiveness and does not put subjects at risk;
• A device intended solely for veterinary use;
• A device shipped solely for research with laboratory animals; A custom device as defined in 812.3(b).

The Office for Research Protections Quality Management Program can help investigators determine if their device study is IDE exempt. Contact them at orp-qm@psu.edu.

For more information on Emergency Use of Unapproved Device, Compassionate Use, and Treatment Use, please see the information provided by the College of Medicine.

Premarket approval (PMA) (21 CFR 814.39) is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices. Due to the level of risk associated with Class III devices, FDA requires sufficient valid scientific evidence to assure that the device is safe and effective for its intended use(s). The content of PMA is similar to the NDA for new drugs, and contains manufacturing sections, pre-clinical laboratory studies and clinical investigations. Some devices (from Class I or Class II) may be able to be cleared under a different pathway referred to as premarket notification, or 510(k). The name refers to requirements outlined in section 510(k) of Food, Drug and Cosmetics Act. If the device is considered to be substantially equivalent to one or more similarly marketed devices (known as “predicate” devices), a claim of substantial equivalence can be made. A claim of substantial equivalence does not mean the new and predicate devices must be identical. Substantial equivalence is established with respect to intended use, design and other parameters.

For more information on Humanitarian Use Devices, see the information provided by the College of Medicine.

The Office for Research Protections Quality Assurance Program is available to assist with IDE preparation, submission, and maintenance. Contact them at orp-qm@psu.edu.

For guidance and templates for your IDE application, see the Quality Assurance Program’s resources.

For privately sponsored studies that are conducted pursuant to a private sponsor’s protocol (industry sponsor), the sponsor of the study is required to pay for the reasonable cost of treating injuries or complications directly resulting from participation in the study, including injuries or complications resulting from the study material or research procedures performed pursuant to the study protocol, to the extent that injuries/complications were not a result of negligence, willful misconduct or failure to reasonably act on the part of the study personnel.

When the trial is not conducted pursuant to a private industry sponsor protocol, the costs of treating study subjects for injuries or complications directly resulting from a study material or research procedures will be the responsibility of the subject or the subject’s Medicare/private insurance plans. In these cases, the IRB requires following language in the consent form to notify participants of their financial responsibility:

"In the unlikely event you become injured as a result of your participation in this study, medical care is available. It is the policy of this institution to provide neither financial compensation nor free medical treatment for research-related injury. By signing this document, you are not waiving any rights that you have against The Pennsylvania State University for injury resulting from negligence of the University or its investigators."

In addition to the information below, please see RPG03 Payments to Human Participants in Research for Penn State guidance on payment methods.

The Institutional Review Board (IRB) should determine that the risks to subjects are reasonable in relation to anticipated benefits and that the consent document contains an adequate description of the study procedures as well as the risks and benefits. It is not uncommon for subjects to be paid for their participation in research. Payment to research subjects for participation in studies is not considered a benefit, it is a recruitment incentive.

Financial remuneration is often used when health benefits to subjects are remote or non-existent. The amount and schedule of all payments should be presented to the IRB at the time of initial review. The IRB should review both the amount of payment and the proposed method and timing of disbursement to assure that either are coercive or present undue influence [21 CFR 50.20]. Any credit for payment should accrue as the study progresses and not be contingent upon the subject completing the entire study. Unless it creates undue inconvenience or a coercive practice, payment to subjects who withdraw from the study may be made at the time they would have completed the study (or completed a phase of the study) had they not withdrawn. For example, in a study lasting only a few days, an IRB may find it permissible to allow a single payment date at the end of the study, even to subjects who had withdrawn before that date. While the entire payment should not be contingent upon completion of the entire study, payment of a small proportion as an incentive for completion of the study is acceptable to FDA, providing that such incentive is not coercive. The IRB should determine that the amount paid as a bonus for completion is reasonable and not so large as to unduly induce subjects to stay in the study when they would otherwise have withdrawn. All information concerning payment, including the amount and schedule of payment(s), should be set forth in the informed consent document.

The role of the IRB is to review and to make determinations on all research involving human subjects. All Penn State employees (faculty/staff/administrators) and students conducting human subjects research need to submit required materials to the IRB for review and approval before beginning any research activity.  For an overview of the IRB submission and approval process, see the IRB website.

Detailed information about IRB policies and the submission and review process can be found in the IRB Investigator Manual.

Your IRB Analyst is your primary contact for each study you submit and will generally remain your contact through the life of a study while open with the IRB. IRB Analysts can help you as you prepare your submission materials and answer your questions about submission and approval. Find your IRB Analyst.

Anyone handling regulated biohazardous materials in teaching or research at Penn State must submit an application to Institutional Biosafety Committee (IBC) before handling the materials. Biohazardous materials include human biological specimens, infectious agents, recombinant material, and gene therapy. Biological toxins and carcinogens are also included if they are used in conjunction with animals.

The Pennsylvania State University Embryonic Stem Cell Research Oversight (ESCRO) Committee is charged with reviewing, approving and overseeing human embryonic stem cell (hESC) research. 

Depending on the nature of your study, the IRB may require other approvals:

Clinical Research Center Advisory Committee: Research involving the use of services at the Clinical Research Center (CRC) for any reason, including the use of personnel as back up to the research team or plans to use personnel in the event of an emergency, need to be reviewed by the CRC Advisory Committee. CRC Advisory Committee approval is not required before the IRB will approve the study.

Conflict of Interest Committee (Individual): Research studies in which a member of the study staff has a financial interest as defined by PSU policies must be reviewed by the Conflict of Interest Review Committee (CIRC-HY). IRB approval will not be granted until the IRB has reviewed the recommended management plan.

Conflict of Interest Committee (Institutional): Research studies in which an institutional conflict may exist as defined by PSU policies must be reviewed by the Institutional Conflict of Interest Review Committee. IRB approval will not be granted until the IRB has reviewed the recommended management plan.

Institutional Animal Care and Use Committee: Research involving vertebrate animals must receive approval from the Institutional Animal Care and Use Committee. Investigators will need to complete an IACUC application. The IACUC approval is required before IRB approval will be issued.

IND/IDE Audit Ancillary Review: Research in which a Penn State researcher holds the IND or IDE or intends to hold the IND or IDE must be reviewed by the Office for Research Protections Quality Management Program to ensure sponsor-investigator is compliant with FDA sponsor requirements (including GMP when applicable). The IND/IDE audit must be completed before IRB approval will be issued.

See the IRB Investigator Manual for a complete list of other approvals required before initiating human subject research.

To learn about IRB approvals associated with multi-site research and external collaborations, see the IRB page on single IRBs and authorization agreements.

When an established patient is being considered for participation in a research study by a clinician involved in the patient’s care, the HIPAA rules can be confusing. HIPAA applies when a provider is reviewing a patient’s medical record for both treatment and research purposes. In general, under the HIPAA privacy rules, a patient’s medical information may be accessed for a treatment, payment or operational purpose without obtaining prior written consent. Access to a patient’s medical record for any other purposes may require additional steps to be in compliance with privacy laws and rules. This means that when a provider looks at his or her patient’s medical record for research purposes, the research-related HIPAA rules apply.

If a patient’s record is reviewed for a treatment purpose (e.g., to view lab results or consult with a referring provider) the research-related rules do not apply. However, once a patient’s medical information is viewed for a research-related activity (e.g., to screen for eligibility or review, to review a unique case for possible study, or to collect data) the research-related HIPAA rules apply. For example, if a provider is reviewing a patient’s lab report for regular care, this access would be for treatment purposes and the research-related rules would not apply. However, if during this review, the provider notices that the lab value may make them a potential research subject and wants to review the chart further for eligibility; the research-related rules would need to be considered.

In general, before any patient information can be used for a research purpose, the patient must sign and date a study-specific consent form that includes the HIPAA authorization elements or a separate HIPAA authorization form which recites the patient’s privacy rights. This is true whether or not the patient is seen by the researcher/physician for medical care. Patient information cannot be used for research-related purposes without a signed patient authorization. There are two limited exceptions: if the IRB has granted a Waiver of Authorization or if the IRB has granted a “Preparatory to Research Authorization.”

Important: Any study data obtained without the proper authorizations cited above may not be used for publication (i.e. journals, abstracts, etc.) or any other purpose and can be subject to notification requirements under state and/or federal laws.

A HIPAA Waiver of Authorization can be obtained from the IRB if access to patient data is needed for recruitment purposes. Describe the need in the “HIPAA Research Authorization and/or Waiver or Alteration of Authorization” section of the protocol template or the protocol site addendum. This section is reviewed by the IRB. If a full or partial waiver is granted, access to identifiable patient data to determine if a patient may be a potential research subject will be authorized. IRB approval is confirmed by issuance of the IRB approval memo for the study. The requirement to obtain authorization may be waived or altered if certain criteria are met. Refer to “CHECKLIST: HIPAA Waiver of Authorization (HRP-441)” in the CATS IRB "Library" for a list of the criteria. Authorization may be waived for all, or only some uses of protected health information (PHI) for a particular study. A partial waiver permits the use of PHI for recruitment purposes only, to allow identification and, as appropriate, contact of potential participants to determine their interest in study participation. The requirement to obtain authorization for use of PHI may also be altered for a specific study. An alteration allows a change in certain authorization requirements, while still requiring authorization for the use of PHI. Examples include making an exception to the required language in an authorization or to the requirement to obtain a signed authorization. An alteration must meet the same criteria as a waiver or partial waiver. To request a waiver or alteration of authorization, you must complete the “HIPAA Research Authorization and/or Waiver or Alteration of Authorization” section in the protocol or protocol site addendum for the study.

Appendix A-11 of the IRB Investigator Manual includes a list of informational elements that are considered to be identifiers according to the HIPAA regulations. For additional information see Penn State policy RP07 HIPAA and Research at Penn State University.

An application for the use of PHI from decedents must be submitted to the IRB prior to engaging in the research. In order to gain access to the PHI, the principal investigator needs to demonstrate that the use or disclosure being sought is solely for research on the PHI of decedents, adequate documentation of the death of such individuals, and that the PHI for which use or disclosure is sought is necessary for the purposes of the proposed research. The “Research on Decedent's Information” form should be submitted as a supporting document in the CATS IRB submission.

Because it may be necessary for a researcher to obtain access to and review PHI in order to prepare a research study, HIPAA rules allow such a review upon compliance with specified criteria. An application for review of PHI preparatory to research must be submitted to the IRB for review and approval.

HIPAA rules require that a record be made of a disclosure of any personally identifiable information that is made without an authorization by the research participant. Therefore, tracking of disclosures will have to be undertaken for all disclosures if a waiver of authorization, an approval for review preparatory to research or an approval for the use of a decedent’s PHI is obtained for purposes of research, and for any disclosures not previously specified in a signed authorization document. For purposes of this policy, “disclosure” means the release, transfer, provision of access to, or divulging in any other manner of PHI to any person, whether or not employed by Penn State, who is not participating in carrying out the research protocol. The following information about any disclosure must be recorded and made available to the individual who is the subject of the PHI upon request:

• Date of disclosure
• Name of person/entity that received the PHI
• Description of what PHI was disclosed
• Brief statement regarding the purpose of the disclosure

If a research protocol requires multiple disclosures to the same outside party over a period of time, the following information is adequate:

• For the first disclosure, all of the above must be recorded
• For subsequent disclosures, tracking can refer to the initial record of disclosure and should include the frequency, periodicity or the number of disclosures that will be made
• The date of the last disclosure must be documented

Large Studies: When tracking is required and involves the disclosure of PHI from more than 50 people, HIPAA rules allow a modified tracking method. In this instance it is unnecessary to maintain a list of the specific persons about whom PHI has been disclosed, but the following information must be available upon the request of any individual whose information may have been included:

• The name and description of all protocols involving 50 or more people for which authorization has been waived, including the purpose of these and criteria for selecting records
• Brief descriptions of types of PHI disclosed
• Dates or time periods during which disclosures occurred
• Contact information (name, address, telephone number) for sponsors and recipient researchers
• Statement that a specific individual’s PHI may or may not have been disclosed for a particular protocol or research activity

In addition, the researcher must also assist in contacting the sponsor and recipient researcher if it is reasonably likely that an individual’s PHI was disclosed to them. Tracking information as required by HIPAA rules must be maintained by the principal investigator at least six years, and made available to the Privacy Officer.

All studies approved or determined exempt by the IRB have reporting requirements over the course of study. For a summary of these requirements, see the IRB webpage on after approval activities. For a more detailed description, see the IRB Investigator Manual.

Note: Typically, if you are notifying a sponsor or the FDA about a protocol amendment or a reportable event, you must also report the same to the IRB. New protocols and a change in protocol must be submitted to and approved by the IRB before the research activities can begin. Unintended or unexpected events or protocol deviations often need reported to the IRB as "reportable new information" within 5 business days.

The ClinicalTrials.gov Protocol Registration and Results System (PRS) is a web-based tool used to submit clinical study information to ClinicalTrials.gov, which is available to the public.

Study registration is required for some FDA-regulated studies, NIH-funded clinical trials, and for publication in over 1,000 journals.

If registration is required, studies approved by the University Park IRB must be registered within 21 days of approval.

Email the Office for Research Protections Quality Assurance Program at orp-qm@psu.edu if you need access to the PRS, need help determining if registration is required, or need assistance registering a study. Also please visit the Quality Assurance ClinialTrials.gov Registration and Reporting website  for more information on what studies are required to be registered and the registration process, including Office for Research Protections policies on registration.

Also check out the ClinicalTrials.gov Infosheet.

REPORTING UNDER IND (PROTOCOL AMENDMENTS)

You need to submit an IND Protocol Amendment if you have either of the following changes during the course of your study:

• New protocol
• Change in protocol
• New investigator (new site)

The study may begin after you obtain IRB approval based on the new or amended protocol and after the FDA receives the amendment. FDA does not issue “permissions” or “approvals” for protocol amendments, your changes are effective immediately upon the receipt of your amendment by the FDA. The IRB may request documentation of FDA review of amendments and may hold approval until documentation is received from the FDA. In these cases, the PI must request that the FDA provide documentation that the research may continue. For changes in the protocol, the IND Protocol Amendment consists of:

• Cover Letter identifying the submission as “Protocol Amendment: Change in Protocol” or “Protocol Amendment: New Protocol”
• Form 1571 – Check an appropriate box under Paragraph 11, “Protocol Amendments”
• A document outlining the differences between the new protocol and the original protocol

For changes in the investigators, the IND Protocol Amendment consists of:

• Cover letter identifying the submission as “Protocol Amendment: New Investigator”
• Form 1571 – Check an appropriate box under Paragraph 11, “Protocol Amendments”
• Form 1572 for the new investigator

If there are manufacturing or other changes, such as:

• Changes in chemistry, manufacturing and control,
• Changes in pharmacology/toxicology (new findings affecting safety and efficacy), or
• Decision to discontinue a clinical study,

the manufacturer (in many cases, industry sponsor) will notify you. Your responsibility is to notify the IRB and make a decision as to whether to proceed with your trial.

REPORTING UNDER IDE (IDE SUPPLEMENTS)

Any changes in the Investigational Plan should be approved by the FDA and, when appropriate, IRB, prior to implementing any change to a previously accepted Investigational Plan. The following types of protocol changes would require an approved IDE Supplement, because they are likely to have a significant effect on the scientific soundness of the trial design and/ or validity of the data resulting from the trial.

• Change in indication
• Change in type or nature of study control
• Change in primary endpoint
• Change in method of statistical evaluation
• Early termination of the study (except for reasons related to patient safety) Change in the number of investigational sites
• Change in the number of study subjects

However, if the modifications meet certain criteria, the sponsor of an IDE may modify the device and/or clinical protocol without prior FDA approval. The sponsor still needs to provide notice to FDA within five working days of making the change. These notices must be identified as a “notice of IDE change.”

Emergency use: If PI deviates from the investigational plan to protect the life or physical well-being of a subject in an emergency. Such deviations should be reported to the IRB promptly after its occurrence, and to the FDA within five working days after the sponsor becomes aware of it.

Certain changes to the device: Advance IRB notification is not required if the changes do not constitute a significant change in design or basic operation and are made in response to information gathered during the course of an investigation. Examples include: creditable data generated under the device control procedures (21 CFR 820.30), preclinical/animal testing, peer reviewed published literature, and clinical information gathered during a clinical trial or marketing.

Certain clinical protocol changes: When they do not affect (i) the validity of the data or information resulting from the completion of the approved protocol, or the relationship of the likely patient risk to benefit ratio relied upon to approve the protocol; (ii) the scientific soundness of the investigational plan; or (iii) the rights, safety, or welfare of human subjects involved in the investigation.

If changes will be submitted in the annual report: A sponsor may make minor changes to an Investigational Plan without prior FDA approval; provided that the respective changes are reported in the annual progress report for the IDE (see Annual Reports).

Contact the Office for Research Protections Quality Assurance Program for assistance: orp-qm@psu.edu.

Note: SAEs, Unanticipated AEs, and Unanticipated Problem Involving Risk to Participants or Others must be reported to the IRB within 5 business days as "reportable new information."

Adverse Event (AE): An adverse event is an undesirable and unintended event occurring as a result of therapy or other intervention (e.g., headache following spinal tap or intestinal bleeding associated with aspirin therapy). It also includes any untoward or unfavorable 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 the research. Serious Adverse Event (SAE): Events are classified as serious if they meet any of the following criteria:

• Results in death or any life threatening event that places the subject at immediate risk of death from the event as it occurred.
• Any event that requires or prolongs in-patient hospitalization.
• Any event that results in persistent or significant disability/incapacity.
• Any congenital anomaly/birth defect diagnosed in a child of a subject who participated in the study and received study drug.
• Other medically important events that in the opinion of the investigator may jeopardize the subject or may require intervention to prevent one of the other outcomes listed in the definition above.

Unanticipated AE: Any adverse experience, the frequency or severity of which is not consistent with the current consent form or investigator brochure.

Unanticipated Problem Involving Risk to Participants or Others: Any unanticipated event involving any aspect of a research study involving anyone (participants, research staff, or others not directly involved in the research) that increases the risk to the person involved. 

DHHS Guidance: Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events

Once an adverse event becomes serious, the site should inform the Sponsor by submitting an SAE report. Typically, the Sponsor will provide the report form to use and inform the study investigator/coordinator where and how (i.e. email, fax, etc.) to send the report. An SAE report should be submitted to the Sponsor no later than 24 hours after the site becomes aware of the event. As the site gains more information (i.e. admission records, hospital discharge summaries) updated SAE reports with the new information should be submitted to the Sponsor. In this case the Sponsor (Industry/cooperative group) holds the IND and is therefore responsible for deciding whether the SAE should be reported to the FDA.

Note: All SAEs must be reported to the IRB within 5 business days as "reportable new information." 

IND SAFETY REPORTS

In cases where the PI is both the Investigator and the Sponsor, the PI assumes the responsibility of reporting certain SAEs to the FDA and IRB. Once it is determined that an SAE must go to the FDA an IND Safety Report is prepared (usually the PI, in association with the medical monitor, will determine whether an IND Safety Report needs to be prepared). An IND Safety Report is an expedited, written notification to the FDA of an adverse experience associated with the use of a study drug that is both serious and unexpected.

When and where to report:

• For any unexpected fatal or life threatening SAE associated with the use of the drug, the IND Sponsor-Investigator notifies the FDA of the SAE by telephone or fax as soon as possible, but no later than seven calendar days after initial receipt of the SAE. The investigator follows with the written report no later than 15 days after the occurrence.
• For serious and unexpected, but non-fatal adverse events, file as soon as possible and no later than 15 days after initial receipt of the SAE.
• All SAEs must be reported to the IRB within 5 business days as "reportable new information."

FDA Guidance: IND Safety Reports

IDE SAFETY REPORTS

An unanticipated adverse device effect is any serious adverse effect on health or safety, any life-threatening problem or death caused by, or associated with a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the application; or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.

When and where to report:

• Report to the device manufacturer as soon as possible but no later than 10 working days after the investigator first learns of the effect.
• Report to the IRB as soon as possible but no later than 5 business days as "reportable new information."

Thereafter the sponsor (or Sponsor-Investigator) shall submit such additional reports concerning the effect as FDA requests. The investigator will submit further information as the IRB request.

FDA Guidance: IDE report details

In many cases Sponsors will specify at the beginning of the study how they would like to handle protocol deviations. Minor deviations (as described elsewhere in this Guidebook) are usually recorded in the case report forms and tabulated by site at the end of the study. Most Sponsors do not require that minor deviations be reported in any immediate fashion. For major deviations the site often reports to the Sponsor are required. In the case where a site needs a deviation in order to enroll a patient that is not otherwise eligible per the protocol inclusion/exclusion criteria, a Sponsor will request that a planned protocol deviation be filed requesting permission from the Sponsor for the site to enroll the patient. Sponsors will respond to this request in writing and this form along with documentation of all communication between the site and Sponsor should be kept in the patient’s source documentation. IRB approval is also needed for these one-time protocol exceptions.

REPORTING PROTOCOL DEVIATIONS UNDER IND

(Information adapted from MAGI Journal of Clinical Research Best Practices) FDA’s regulations have numerous references to “changes” or “amendments” to study protocols. For example, 21 CFR 312.30 addresses the responsibility of sponsors to submit amendments to their IND(s) to ensure that clinical investigations are conducted according to protocols included in the application. 21 CFR 312.30(b) specifically discusses changes in a protocol, and provides several examples of changes that would require sponsors to submit protocol amendments to the IND. However, the FDA regulations do not provide specific guidances on deviation reporting.

A protocol deviation directed at eliminating an apparent immediate hazard to a research subject or group of subjects may be implemented immediately but must be reported to the IRB as "reportable new information" as soon as possible but no later than 5 business days.

The respective protocol deviation should be addressed in the next Annual Report to the IND application. If the protocol deviation will be incorporated as a permanent change (i.e., revision) to the protocol, a respective Protocol Amendment must be submitted prospectively to the IND application/FDA. The revision to the protocol must be approved by the IRB before it can be implemented.

REPORTING PROTOCOL DEVIATIONS UNDER IDE

FDA device regulations at 21 CFR 812.150(a)(4) discuss protocol deviations under IDE regulations. An investigator shall notify the sponsor and the IRB of any deviation from the investigational plan to protect the life or physical well-being of a subject in an emergency. Such notice shall be given as soon as possible but no later than 5 days after the emergency occurred. Except in such an emergency, the IRB must approved protocol deviations, or changes, before they can begin. The FDA must be made aware in accordance with 21 CFR 812.35(a).

ANNUAL REPORTS TO CDER

For clinical trials being conducted under an IND, FDA requires an annual report from the Sponsor or Sponsor-Investigator. The annual report is due within 60 days of the anniversary date that the IND went effect (i.e., the date that the FDA permitted the study to begin). Required content is listed in 21 CFR 312.33.

ANNUAL REPORTS TO CDRH

For clinical trials being conducted under an IDE, FDA requires Sponsors to submit progress reports, at regular intervals, and at least yearly. Reports must be submitted to all reviewing IRBs and in the case of significant risk devices the sponsor must also submit the progress report to FDA (21 CFR 812.150).

Contact the Office for Research Protections Quality Assurance Program for assistance: orp-qm@psu.edu.

“Essential documents are those documents which individually and collectively permit evaluation of the conduct of the trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.” (ICH Guideline E6) There are many ways to organize essential documents, and there is no gold standard for how to do this. For example, the ICH GCP E6 guideline recommends that the documents be grouped according to the stage of the trial, i.e. documents relevant to the trial before it commences, documents relevant to the trial during the conduct of the trial, and those documents relevant to the trial after completion or termination of the trial. See specific information here. The most important thing is that the documentation is organized and that all of the necessary documents are present. This section of the Guidebook provides examples of a potential system to organize essential documents. Essential documents also serve a number of other important purposes. Filing essential documents at the investigator/institution and sponsor sites in a timely manner can greatly assist in the successful management of a trial. These documents are also the ones which are usually audited by the independent audits and inspected by the regulatory authority(ies) as part of the process to confirm the validity of the trial conduct and the integrity of data collected. Another way to organize the essential documents into study binders is by the content of the binder. For example, many sites have a “source document binder,” a “case report form binder,” a “financial binder” and a “regulatory binder.”

Industry sponsors may provide investigators with a regulatory binder to be used to maintain the essential documents for the trial. Investigators who are conducting investigator-initiated trials are encouraged to use the Penn State's REDCap eRegulatory Binder for electronic storage and organization of regulatory documentation.

The eRegulatory Binder can be used alone or alongside the use of paper records. Additional information regarding access and utilization of the REDCap eRegulatory Binder can be found at the Office for Research Protection Quality Assurance website.

The following list represents the required essential documents that must be filed in the regulatory binder. All essential documents must be available for audit/inspection by the sponsor and regulatory authorities. The eREgulatory Binder provides all essential tabs and information about what needs to go under each tab.

See also the Regulatory Binder – Documentation Checklist.

It is common practice for investigators to delegate certain study-related tasks to employees, colleagues, or other third parties (individuals or entities not under the direct supervision of the investigator). However, the Principal Investigator (PI) is ultimately responsible for the conduct of the study. When tasks are delegated by an investigator, the investigator is responsible for providing adequate supervision of those to whom tasks are delegated. A Delegation of Authority log should be created documenting delegated tasks to delegated individuals. The same applies to staff/contract organizations not in direct employ of the investigator.

Title of the study

Below the log, the PI should sign and date.

Per ICH GCP guideline E6 section 5.1 source data is identified as “all information in original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.” This is the first recording of subject-related information. According to 21 CFR 312.62(b), and investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual. Source documents must be complete, accurate, and valid. The regulatory authorities consider source documents to be the basis for al trial data and the adjudication of the outcome of events. The purpose of source documents/patient record binder:

• To document the existence of the participant and substantiate integrity of trial data collected.
• To include original documents related to the trial, medical treatment, history of participant, and participant’s condition while on-study or in follow-up. To provide an auditable link in the chain from the study database back to the original source (visit worksheet).
• To collect data for transfer to CRFs and then to the study database.
• To instruct study coordinators and other site personnel on what data to collect and information necessary to answer data queries.

These can be electronic media, original documents or certified copies. The following Source Document Binder Table of Contents is adopted from Partners Healthcare.

According to ICH GCP EC 1.11, a case report form is a printed, optical, or electronic document designed to record all of the protocol required information to be reported on each trial subject. CRFs are designed by the sponsor or sponsor-investigator and maintained at the investigative site. Information documented on the CRF (or eCRF) must be supported by source documentation. At a minimum the CRF should record:

• Inclusion/exclusion criteria and assessment as to whether the subject met them
• Protocol-specific clinical laboratory testing (including EKGs, X-rays, eye exams, scans, etc.) documented by laboratory records
• All AEs, SAEs, concomitant therapies, and/or inter-current illnesses
• Assessment of severity of AEs, relationship to test article, and expectedness of the AE
• Report of all dropouts and the reasons

One of the most essential tasks performed by the Clinical Research Coordinator (CRC) is completing and/or ensuring the completion of the subject’s CRF. Most sponsors will provide instructions or a guide for CRF completion. Handwriting must be legible and should be completed in black ink. All data points must be addressed and for fields that cannot be completed, “not available,” “not done” or “unknown” should be marked in accordance with the sponsor’s instructions. The CRC will ensure that all required data are collected and entered on the CRF as soon as possible after, if not during, the visit. All CRFs should be checked for completeness and legibility. The CRFs should be reviewed and signed by the investigator prior to submission. Only those physicians identified on the 1572 may sign CRFs. When making a correction on a CRF, a single line should be drawn through the incorrect entry and the correct data should be entered above or next to the incorrect entry. The correction should be dated and initialed. White-out or eraser should never be used to correct an error. Blanks identified prior to the investigator’s review and sign-off on the CRF can simply be completed. Those identified after sign-off must be dated and initialed.

To learn more about the study financial binder, see the information provided by the College of Medicine.

College or unit research administrators assist investigators in maintaining financial records.

Prepare for an Audit

An audit is a systematic and independent examination of trial-related activities and documents to evaluate whether the trial-related activities were conducted and the data were recorded, analyzed and accurately reported according to the protocol, Sponsor’s SOP, GCP and other applicable regulatory requirements. Auditors collect evidence and compare against standards, review documents, assess deviations and non-compliance and recommend actions.

Contact the Office for Research Protections Quality Assurance Program for assistance: orp-qm@psu.edu.

Additional Resources:

The Penn State Health (PSH) Clinical Trial Monitoring services are now available for researchers outside of the College of Medicine and Penn State Health system.  PHS Clinical Trial monitoring services are fee based and include:

• Creation of a customized data monitoring plan
• Source document verification
• Review of regulatory documents
• Tracking of investigational products
• Data monitoring visits

A description of the DPHS Clinical Trial Monitoring Services available to Penn State investigators is included in the DPHS Data Management Services website at https://med.psu.edu/phs/services

The Bioresearch Monitoring Unit of the FDA may conduct inspections of medical research and testing facilities in order to ensure studies avoid bias and follow proper testing procedures. The FDA inspector will review all case study data and may interview subjects and doctors. In all types of inspections, an FDA inspector checks the study for errors that affect the outcome. Investigators may expect the following types of inspections:

• Routine Inspection may be conducted at random. It is sometimes triggered by abnormally high enrollment rate as well as large studies to promote a pivotal drug.
• For Cause Inspections: FDA investigator has a reason to check out a research facility, i.e., subject complaint, a highly publicized drug, unqualified investigators, large AE clustering.

Once you receive notification of the FDA audit notify the appropriate research administration offices, including the IRB. Specific procedures to follow when preparing for an inspection and on the day of the inspection will be discussed with the research team prior to the inspection date.

FDA Guidance: FDA Inspections of Clinical Investigators

The Office for Research Protections Quality Assurance Program conducts directed audits, routine audits and quality improvement assessments. The purpose of routine reviews is to assist investigators with achieving high quality of regulatory compliance. The reviews are meant to be educational and prevent any potential instances of non-compliance. Quality Assurance summarizes and reports the findings directly to the investigators. For more information, go to the Quality Assurance Post-approval Reviews website.

Account Closure or Extension Forms (ACE Forms) are sent to the financial contact -- usually a college or department research administrator -- when an account has an end date in the accounting system. The Controller’s office receives a restricted fund report from Research Accounting at University Park with accounts that have end dates. The financial contact works with the investigator and study team to either extend the end date if the contract allows, request an amendment from the sponsor or close out the account in the accounting system.

College or unit research administrators assist investigators in closing accounts in IBIS.

You can close a study with the IRB when it meets four conditions:

• The protocol is permanently closed to enrollment at this institution.
• All subjects enrolled at this institution have completed all protocol-related interventions and interactions, including interventions and interactions related to collection of long-term follow-up data.
• No additional identifiable private information about the subjects is being obtained by this institution’s investigator.
• Analysis of private identifiable information at this institution is completed.

At any time, close a study by submitting a Continuing Review, even if continuing reviews are not required for the study. In the submission, indicate that the four milestones have been met.

For more details, see the IRB Investigator Manual.

Once the project is terminated by the sponsor or the grant or contract end date expires, the Controller’s Office receives a monthly report from Research Accounting. The Controller’s Office notifies the appropriate financial administrator for closeout or extension and provides an Account Closeout/Extension (ACE) form for completion. Once the financial administrator returns the ACE form to the Controller’s Office, the Controller’s Office notifies OSP of the expiration. OSP updates the SIMS database. The PI and department must retain the project records for the period of time designated in the agreement.

College or unit research administrators assist investigators in this process.

For drugs, according to 21 CFR 312.62(c), an investigator shall retain records required to be maintained under the part for a period of two years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the applications is not approved for such indication, until two years after the investigation is discontinued and FDA is notified. For devices, according to 21 CFR 812.140(d), an investigator or sponsor shall maintain the records required by this subpart during the investigation and for a period of two years after the latter of the following two dates: the date on which the investigation is terminated or completed, or the date that the records are no longer required for purposes of supporting a premarket approval application or a notice of completion of a product development protocol. Study Sponsors may have additional document retaining provisions stipulated in the Contract.

The National Institutes of Health (NIH) requires researchers to acknowledge federal funding in peer-reviewed publications by citing any NIH grants that supported the research process described in the publication. In addition, the NIH Public Access Policy requires that all investigators “funded by the NIH,” be it through direct funding or through use of resources of an NIH-funded center (such as Penn State Clinical and Translational Science Institute) submit an electronic version of their final, peer-reviewed manuscripts to PubMed Central (PMC) upon acceptance of publication. This policy ensures that the public has access to the published results of NIH-funded research. Failure to submit the manuscript to PMC within NIH-imposed deadlines may result in a delay of processing the grant awards of the researchers or centers whose grants were cited in the manuscript.

RESOURCES ABOUT COMPLYING WITH THE NIH PUBLIC ACCESS POLICY

• Details of the NIH PublicAccess Policy
• Directions and tutorials for submitting a manuscript to PMC through the NIH manuscript submission system
• Information about citing the CTSI in a publication