Research Staff Training Part 1There are many facets of clinical research. The following will provide you with a good knowledge base to build upon when we address the Standard Operating Procedures of Beyer Research in Part 2 of your training. I encourage you to use the links within this section to enhance your understanding of these subjects. I look forward to answering any questions you may have. Congratulations for choosing an exciting career and welcome to Beyer Research! Sincerely, Lucy Wright Pelletier, CCRC, CPT, CET Director
Clinical Research—An Overview
Drug Development Process
The drug development process is time consuming and expensive. It is estimated that of the 5, 000 new molecular entities (NME) developed; only 5 make it to clinical testing and only 1 of the 5 actually receive FDA approval.
The goal is to find better ways to prevent, detect, and treat diseases. Once a new molecular entity (NME) is tested in vitro and proved to be a hopeful compound, the compound is then tested in animal models to determine the pharmacologic and toxicology effects in specific animal models. The key focus of animal testing is to understand the absorption, distribution, metabolism and excretion (ADME). The goal of preclinical development is to determine if the product is reasonably safe for initial use in humans, and if the compound exhibits pharmacological activity that justifies commercial development.
- Drug Development Timeline
- FDA: How Drugs are Developed and Approved
- FDA: Information for Consumers (Drugs)
- Understanding Clinical Trials
- FDA: Types of Applications
Investigational New Drug (IND):
The IND is an application that sponsors must submit to the FDA to receive an exemption to transport or distribute drugs across state lines. The IND must state the purpose to test the agent in human subjects and supply pre-clinical data and justification to warrant clinical studies. The application must be submitted prior to the start of any human subject research studies. The research study cannot begin participant recruitment until 30 days after FDA receipt or after all FDA requests have been fulfilled. INDs require annual updates to reflect protocol changes, new information, or serious adverse events.
Phases of Clinical Trials
Phase I Trials
Phase I clinical trials are conducted to determine the safety and tolerance of study agents in normal healthy participants, with the exception of serious and life threatening conditions such as cancer or HIV. These studies are often known as the “first in man” studies because they are the first introduction of an investigational new drug to humans. Understanding how the drug is metabolized and excreted is usually the scientific focus of these studies. Pharmacology, pharmacokinetics, physiological side effects, bioavailability, bioequivalence and establishing the maximum tolerated dose (MTD) are common data elements collected and analyzed. Phase I trials are usually short term studies that include less than one hundred participants.
Phase II Trials
Phase II clinical trials are conducted to determine the safety and efficacy of a drug within a particular disease or specific patient population. These trials are often referred to as Pilot (determine efficacy) or Pivotal (determine efficacy and safety to include in the New Drug Application [NDA]). Efficacy, safety, pharmacokinetics, drug-drug interactions, drug-disease interactions, bioavailability and physiological side effects are common data elements collected for these studies. Phase II trials usually include hundreds of participants.
Phase III Trials
Phase III clinical trials are conducted to confirm or expand the data collected on the efficacy, safety, risk-benefit ratio, long term effects, tolerance and adverse events. The primary objective of a phase III trial is to demonstrate or confirm therapeutic benefit to support the marketing approval of the drug for a specified patient population. Phase III trials usually include hundreds to thousands of participants and include long term data collection. The trials commonly include multiple treatment groups, with control groups such as standard of care comparative drugs or placebo.
Phase IV trials are post market trials. These trials generally are conducted to determine pharmacoeconomic, epidemiologic, adverse event and quality of life data. Phase IV trials usually include thousands of participants in the marketed populations.
- Good Clinical Practices GCP ICH E 6
- ICH E 10: Choice of Control Group and Other Related Issues in Clinical Trials
New Drug Application (NDA)
The New Drug Application (NDA) is the formal request of a sponsor for FDA review and approval of a new drug for commercial sale and marketing in theUnited States. This application encompasses all data gathered during pre-clinical and clinical research. The goal is to show that the drug is safe and effective for the proposed indication and patient population. Details regarding potential side effects, absorption, metabolism, risks, benefits, drug composition, manufacturing details and packaging are all included in this application.
Device Development Process
The FDA defines a medical device as “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:
- recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them,
- 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 which does not achieve any of it’s 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.”
The Center for Devices and Radiological Health (CDRH) is a center within the Food and Drug Administration (FDA) that regulates and approves medical devices sold in theUnited Statesalong with medical and non-medical radiation emitting products. Devices containing drugs, biologics, or radiating emitting devices may also fall under the jurisdiction of one of the other FDA centers and be subject to additional regulations.
Medical devices distributed in the United States must comply with the following regulatory requirements: Establishment Registration; Medical Device Listing; Premarket Notification 510(k), unless exempt, or Premarket Approval (PMA); Investigational Device Exemption (IDE) for studies; Quality Systems Regulation; Labeling Requirements; Medical Device Reporting (MDR).
Device development regulations are filled with exceptions, exemptions, and special classifications. For example, devices being tested to determine consumer preference can be exempt if they are not intended to establish safety or effectiveness. Veterinary and laboratory animal research devices are exempt when used solely for those purposes. Humanitarian Device Exemptions (HDEs) can be granted if a device is being used in a condition that affects less than 4,000 people a year in the U.S. Expanded access can be granted for compassionate use, treatment use, continued access, or emergency use.
If a device manufacturer does not have a device that is exempt from the regulatory requirements they either have to complete a Pre-Market Notification 510(k) or a Premarket Approval (PMA). If the 510(k) or PMA requires clinical data to support the application an Investigational Device Exemption (IDE) may also need to be filed.
FDA Regulatory Resources
- CDRH Training and Education Resources
- CDRH Guidance Documents
- Device Advice
- Overview of Device Regulations
Devices are classified into three categories. Class I devices are low risk that require general controls to assure safety and effectiveness. Class II devices have moderate risk and are subject to both general and special controls. Class III devices are considered high risk and are subject to the highest level of regulatory requirements. The FDA has exempted almost all Class I devices with the exception of some listed as “Reserved Devices” from the PMA requirements. Some Class II devices are now exempt from Pre-market notification requirements due to the 1997 FDA Modernization Act. All Class III devices and those that do not meet the criteria for exemption or a 501(k) require a PMA.
Premarket Notification 510(k)
Devices that require a 510(k) cannot be commercially distributed until the FDA provides authorization. To receive authorization the manufacturer must demonstrate in the notification that the device is substantially equivalent to a predicate device. Predicate devices were on the market prior to May 28, 1976 or are currently on the market and do not require a Pre-market Application (PMA) to be completed.
A device is substantially equivalent if it has the same intended use as a predicate device and has the same technological characteristics or it has the same intended use as the predicate device and has different technological characteristics as a predicate but safety and effectiveness can be demonstrated.
If a device does not meet the criteria for a 510(k) then the manufacturer must submit a PMA application. If a clinical study is needed to support the application then an IDE may also be needed.
Investigational Device Exemption (IDE)
All clinical studies of devices must either have an approved IDE or be exempt from the regulations. The need for an Investigational Device Exemption (IDE) depends upon the level of risk associated with the use of the device. Devices are considered as either Significant Risk (SR) or Non-Significant Risk (NSR) devices.
Significant Risk (SR) Devices must follow full IDE requirements and require both FDA and IRB approval before studies can begin. Non-Significant Risk (NSR) devices are those that do not meet the criteria for significant risk. NSR devices have reduced regulatory requirements and only need IRB approval before studies can begin. IRB approval is considered equivalent to IDE approval for NSR device studies.
Premarket Approval (PMA)
The PMA is the most stringent application for devices and requires FDA approval before the manufacturer can market their device. In the PMA process the FDA is evaluating the scientific integrity of the clinical data being used to support the safety and efficacy of the device.
The protocol development process should be well thought out and include expert consultations in the areas of statistical analysis, data management, clinical care, statistical analysis methods, basic research, and regulatory affairs. Key areas of discussion should focus on defining study objectives, variables, control group, blinding, stratification, study populations, inclusion/exclusion criteria, primary and secondary analysis, data collection points, ethics, risk/benefit ratio, study calendar, and the feasibility of executing the study-required procedures.
- Quantitative Research Design
- Types of Research Designs
- CTEP: Clinical Trial Design and Interpretation of Results
- ICH E6: Good Clinical Practices
- ICH E8: General Considerations for Clinical Trials
- ICH E9: Statistical Principles for Clinical Trials
- ICH E10: Choice of Control Group and Related Issues in Clinical Trials
- Adaptive Design Clinical Trials for Drugs and Biologics
Common Terms in Study Design
Un-blinded – refers to when the participant, investigator and evaluator [i.e. sponsor] know what treatment the participant is receiving; occurs in open label studies.
Single blind – refers to when one of the parties, the participant, investigator or evaluator do NOT know the treatment.
Double blind – refers to when two of the parties do not know what treatment the participant is receiving (Participant & Investigator or Evaluator). This process reduces the possibility of study bias towards rating scales or clinical impressions of improvement. (Participants on active drug might report more favorable responses, staff may be less likely to identify and report responses in no-treatment groups etc.)
Double dummy – is used to blind two agents that are not similar in appearance. Participants take both dosage forms, one is active and one is placebo.
Parallel group – is when participants receive one treatment for a defined time period.
Crossover – occurs when participants receive more than one treatment during a study. Participants take each treatment for a defined period of time. A washout period, where participants take no treatment usually precedes a change in the treatment.
Factorial – occurs when participants receive one of multiple treatments for a defined time period and serve as their own control
Survival – participants receive one or more treatments until an event occurs.
The major purpose of control groups are to allow for identification of changes in symptoms, signs or even morbidity caused by the study medication to be discerned from natural disease progression, participant/research staff expectations, or other treatments.
Uncontrolled – study does not contain a control group
Placebo – used when study compares one or more active treatments to a dosage form that does not contain an active ingredient.
Active – when a study compares two or more treatments that contain different active ingredients.
Historical – when a study compares observations from a current study with similar studies that were previously conducted.
No treatment – when a study compares two groups and only one group receives treatment.
Randomization – is used to equally assign participants to treatment groups, eliminating the need for the investigator to choose which treatment the participant should receive. This process eliminates study bias. Many times randomization is handled through an automated telephone system, other times it may be handled through labels or some other mechanism.
Stratification – is used to control treatment group assignment of participants based on a variable thought to affect the study outcome (a study that is using 2 –10 years olds may be stratified to participants 2-4 years, 5-7 years and 8-10 years; can also be stratified in treatment groups/treatment arms)
Evaluates the actions of a drug in the human body throughout certain time points and provides information on the drugs’ absorption, distribution, metabolism and excretion. Usually occurs in phase I/II studies.
Evaluates physiologic effects of a drug in the human body through procedures such as heart rate, blood pressure or ECG. Usually occurs as Phase I/II studies.
A retrospective chart review is a systematic investigation of pre-existing information in a medical record which is limited to the information existing in the medical record. In a prospective chart review the investigator plans to collect and evaluate data that does not exist at the time of the study design.
A descriptive study of an individual person, small group or event reported as an interesting occurrence in which conclusions are only generalizable to the individual or group described.
Allowance by FDA to provide investigational drugs to individual patients for the treatment for serious or life threatening disease, such as cancer or aids, where no other comparable or satisfactory drug treatment is available. The treatment must not pose unreasonable risks and may be effective. This requires a protocol with an investigator’s brochure, IRB approval and informed consent.
When there is not enough time for anINDsubmission to the FDA, the FDA may allow a one-time shipment of the drug prior to the application submission. The detail in the protocol is limited. Sponsor of the study must make anINDsubmission as soon as possible. IRB approval is required within 5 days of drug administration.
These studies are ONLY available to patients who are not eligible to participate in a trial being conducted under anINDand have no therapeutic alternatives. The detail of the protocol is limited.
Planned Emergency Research
Research involving human subjects who are in need of emergency medical intervention (e.g., comparison of methods for providing cardiopulmonary resuscitation), but who cannot give informed consent because of their life-threatening medical conditions and who do not have an available legally authorized representative to provide consent.
Responsibilities of the Research Team
Principal Investigator (PI)
The Principal Investigator has the primary responsibility for ensuring the ethical conduct of the research study. This includes protecting human subjects’ rights, safety and welfare, protocol compliance, and adherence to institutional, state and federal regulations and guidance. The PI is responsible for ensuring informed consent is appropriately obtained from each participant and for appropriately maintaining study records. The PI is also responsible for complying with the financial and administrative policies and regulations associated with the award, overall fiscal management of the project, and conflict of interest disclosure.
- 1572 Statement of the Investigator
- 21 CFR 312.60: General Responsibilities of Investigators
- 21 CFR 812.100: Responsibilities of Investigators: Biologics
- 21 CFR 812.110: Responsibilities of Investigators: Devices
- DHHS: Office of Human Research Protections (OHRP): Frequently Asked Questions
- ICH E6: Good Clinical Practice
The PI oversees all aspects of a clinical trial from protocol design (in investigator initiated protocols), recruitment, data collection, analysis and interpretation of results, but some tasks can be delegated to other research team members (Co-Investigators and Key Personnel). The PI is responsible for ensuring that all research team members have appropriate education, training and qualifications to assume delegated study tests. All study team members are responsible for ensuring that the conduct of the study is compliant with institutional, state, federal and industry guidance and regulations.
Sub-Investigator (Sub-I) / Co-Investigator (Co-I)
The Sub-Investigator/Co-Investigator may perform all or some of the PI functions, but they do not accept primary responsibility for the research study.The sub-investigator/co-Investigator is under the supervision of the PI and is responsible for performing study–related procedures and /or to make important study-related decisions in compliance with the ethical conduct of the study.
The Regulatory Coordinator is typically responsible for drafting or editing the protocol document and submitting new protocols, protocol amendments, continuing reviews and safety reports to the appropriate IRB for review. They are responsible for maintaining regulatory binders in accordance with sponsor specifications and general industry standards. They often are the keepers of the delegation of authority log for key personnel involved in the study.
The Data Coordinator is responsible for the overall data management of a research study. Data points for analysis must be extracted from multiple source documents and entered into specific databases. Data coordinators ensure accurate and timely data entry in electronic databases, electronic case report forms (eCRFs) or paper case report forms (CRF). They work closely with sponsor monitors and resolve any data queries that may be generated. They also work closely with the research team in the study development process to identify key data points for collection and analysis for investigator initiated trials.
Research Coordinator/ Research Assistant
The Research Coordinator/Assistant oversees and coordinates the daily activities of clinical research studies. They work closely with the clinical teams and investigators to ensure that all protocol required procedures and visits occur according to protocol specified guidelines. Research Coordinators/ Research Assistants generally manage participant enrollment and ensure compliance with the protocol and other applicable regulations. This includes but is not limited to; participant recruitment, obtaining informed consent, educating participants on the details of the research study, assessing participant eligibility, facilitating participant care and follow-up per protocol, creating source documentation, assisting in the assessment of toxicities/adverse events and reporting serious adverse events per IRB and sponsor requirements
Research teams interested in contract opportunities with pharmaceutical or device companies contact study sponsors to discuss study availability and the feasibility of being selected as a study site. A pharmaceutical or device company is typically called the industry sponsor when they are the source of funding for the study. There are a lot of pharmaceutical, device, biotech and contract research organizations (CROs) that conduct research studies. Often networking with peers who are already established with conducting industry research studies may be helpful in identifying a sponsor with a clinical trial of interest.
A new site may wish to sign up for a clinical trial listing service, such as Centerwatch. Centerwatch provides services to help sponsors, CROs and service providers identify clinical trial sites. The site can list their information, for a fee. Sponsors and CROs may also have their own databases that sites can enroll in for free such as the Duke Clinical Research Institute.
There can be steep competition for good studies. The key to finding sponsors and good studies is to get on the sponsors “Preferred” list. Preferred sites are those that perform well by being able to start up quickly, enroll the required number of participants, and provide quality data. Sponsors often ask a “Preferred” site if they are interested in new studies before identifying other study sites.
Site Interest Letters & Questionnaires
When study sponsors are recruiting sites to participate in their research studies, they will often send out interest letters and/or questionnaires to potential sites. The sites that they approach are often sites that the sponsor or coordinating center has worked with before or through other recommendations.
When a site interest letter or questionnaire is received, it is usually accompanied by a brief protocol synopsis. In other cases, it could be sent with a Confidentiality Disclosure Agreement (CDA) and full protocol.
Site questionnaires are to be completed by sites in a relatively short amount of time and are meant to provide basic information to the study sponsor in order for them to perform a cursory evaluation of the potential site. Often the questionnaires request basic demographics such as investigator, sub-investigator, study coordinator, and pharmacy information, as well as details of the institution’s IRB. Questions specific to the therapeutic area being studied and expected enrollment numbers may often be requested, too.
Confidential Disclosure Agreements
In order to ensure the protection of confidential information shared for research studies between the research site and a sponsor, a Confidential Disclosure Agreement (CDA) or Non-Disclosure Agreements (NDAs) may be executed. These contract agreements are handled by the Director of Clinical Research.
These agreements can only be executed by individuals with signature authority for each party. At Beyer Research, only the Dr. Beyer, Susan Wright, and Lucy Wright Pelletier have this authority.
It is important that PIs and other research team members of the studies do not disclose confidential information to others outside of Beyer Research without a CDA. Each individual involved in the study should be aware if there are confidentiality agreements in place and be familiar with the specifics of those agreements. In particular, what kind of information can be shared, when it can be shared, in what manner and with whom.
Assessing Protocol Feasibility
Once a Confidential Disclosure Agreement (CDA) is executed, a sponsor will then send the final protocol to the site for review and determination on whether or not the site would like to move forward with the site selection process and participation. When investigators are approached to have their site participate in a new research study, it is important to assess the scientific value and feasibility of managing the study. It is helpful to start by assessing the scientific integrity of the protocol. Is the protocol written well, does it have sound statistical analysis methods, are the end points answering a scientific question of value, is the protocol realistic and ethical to perform for the chosen patient population, are there competing protocols currently open to accrual, is there an opportunity for scientific publication and authorship, will this lead to strengthened collaboration with the sponsor for future research studies of greater scientific value?
The ability to manage the study from an operational standpoint also needs to be assessed. It is helpful to assess the need for additional resources to execute the protocol related activities, overall complexity of the protocol, time commitment to serve as the PI for the trial, adequacy of patient population and ability to meet recruitment requirements, additional training necessary, additional need for space, availability of equipment, costs to conduct the study, funding resources available and any issues with research billing and insurance coverage.
Principal Investigators and/or Research Staff should not agree to participate in a study until a financial analysis has been completed to ensure all anticipated expenses will be covered by the projected budget.
Research Study Budget Design & Analysis
To properly negotiate budgets for research studies it is important to assess protocol feasibility and identify the costs to conduct the study. A study should not be pursued if it does not cover the costs to conduct it, unless there are additional financial resources identified.
The first step to create a comprehensive budget is to develop an internal budget. Internal budgets are used for sites to identify all of their costs to conduct a study and can be used as a tool to negotiate the sponsor budget. It is critical to have a thorough understanding of the study documents to develop a comprehensive budget. This entails reviewing the protocol, contract, consent, and case report forms to identify each procedure, visit, participant contact, supplies, and patient care costs that are needed to conduct the study. It is recommended to identify the work that is required per participant. All of the identified items should be listed in the internal budget.
Once all items are identified to conduct the study, a determination needs to me made if the service is considered Standard of Care (SOC) or Research Only. Standard of Care services are those that are typically performed in the participant population for the disease being studied and will be billed to the patient/insurance. Research Services are those that are performed for research purposes only. Research services are NOT billed to the patient/insurance.
It is important to note that one size does not fit all when it comes to budgeting. There are many different types of studies and sponsors who all have different budgeting needs. There are, however, common core components to developing any study budget. Core budget components include: administrative costs, travel, staff costs, supplies, equipment, patient care costs, etc. There may also be a need for cost sharing or subcontracts.
Administrative and Start up Costs
Administrative costs may include: pharmacy fees; IRB fees, Institutional review fees, shipping expenses, photocopying, office supplies, parking fees, subject meals, phone lines, long distance charges, and storage expenses. Facilities and Administrative (F&A) or Overhead costs also need to be considered. F&A costs are those costs associated with providing and maintaining the infrastructure that supports the research enterprise (buildings and their maintenance, etc…) and which cannot easily be identified with a specific project.
It is customary to request one time, up front, non-refundable fees to cover the cost to prepare a study to start. The idea is to get paid for work completed, even if the study does not start. Sites must also remember to include one time fees for the Institutional Review Boards.
If a study requires travel to investigator meetings or training meetings those costs not pre-paid for by the Sponsor should be included in the budget (i.e., wages for all staff attending the meeting).
When preparing the budget, it is important to identify the types of personnel involved in the study such as; Investigators, Sub-investigators, research coordinators/nurses, research assistants, patient recruiters, etc..
Staffing costs may include the time it takes to attend the start-up meeting, prepare regulatory documents, prepare the budget, screen/recruit participants, obtain informed consent, schedule visits, complete CRFs, complete AE/SAEs forms, manage events, attend mandatory educational classes/training, attend monitoring visits, correct CRFs, answer queries, track lost to follow-up/no-shows, on call time, and study close out.
Supplies and Equipment
Common supplies include paper, pens, folders, binders, labels, table dressings, shipping materials, etc. Equipment such as -70 Freezers or special imaging scanners may also be needed for certain studies.
Patient Care Costs
- Patient care costs include tests and procedures that are required only because the patient is participating in a research project – they are not a part of routine medical care and will not be billed to a patient or a patient’s insurance company.
- Other patient care costs can be considered as “standard of care” and billed to the patient or the patient’s insurance company. These are only for procedures or tests that are not being covered by the protocol’s budget. The billing for any research patient will be determined by the P.I.
- A subcontract may be required if part of the research effort under a grant or contract is to be performed by another organization. An example would be the use of an outside source, such as a radiology center.
Negotiating the Budget
Budgets are negotiated by the Director of Clinical Research and then approved by the P.I. This is done by making a comparison of the internal budget to the sponsor proposed budget. If the sponsor budget does not cover the site’s costs to conduct the study propose changes to the budget. Some sponsors will state that the budget is non-negotiable but it is always worth trying to negotiate to cover costs. Sponsors tend to become more willing to negotiate once a site has developed a proven track record of conducting quality studies.
Clinical Trial Agreement
A Clinical Trial Agreement (CTA) is a legally binding agreement that manages the relationship between the sponsor that may be providing the study drug or device, the financial support and /or proprietary information and the institution that may be providing data and/or results, publication, input into further intellectual property.
It is important to have a CTA for allocation of risk, responsibility, funds, obligations, and the protection of academic, legal, intellectual property and integrity.
A clinical trials agreement should describe and acknowledge responsibilities, terms of collaboration, requirements for payment and reimbursement, publication and intellectual property terms, indemnification and or insurance, subject injury coverage, guidelines for dispute resolution, grounds for termination of contract, and possibility of amending contract terms in the future.
It is important to review the template for monitoring, adverse event reporting, clinical supplies and accountability, requirements for invoicing if applicable, payment disbursement, study close out and data archiving terms.
It is the responsibility of the Director at Beyer Research to negotiate the terms of the CTA and to have them ultimately approved by Dr. Beyer and Susan Wright before the contract is executed.
Human Subjects Research Regulations
The priority of Beyer Research is to protect the welfare of human subject participants in research. This is accomplished by maintaining compliance with the federal and state regulations governing the protection of human subjects, and by facilitating the research efforts of Investigators and research staff through education, training and monitoring
Human subjects research is either determined to be exempt or non-exempt from Institutional Review Board (IRB). IRB approval is based upon a set of federal regulations; either the Department of Health and Human Services (DHHS), the Food and Drug Administration (FDA), or both depending on funding and research activities.
The link below contains detailed information regarding the federal regulations, ethical principles and policies regarding human subjects research.
CITI is required training for all Beyer Research staff. Please consult with your trainer to obtain proper access (which will be given through the Society of Clinical Research Professionals, or SCRS).
FDA Regulatory Resources
- FDA Regulations
- Protection of Human Subjects 21 CFR 50
- Institutional Review Boards 21 CFR 56
- Investigational New Drug Application 21 CFR 312
- Investigational Device Exemptions 21 CFR 812
- FDA Information Sheets
Good Clinical Practices/International Conference on Harmonization
Good Clinical Practice (GCP) is an international ethical and scientific quality standard that was developed by the International Conference on Harmonisation (ICH). The ICH is made up of regulatory authorities from the European Union,Japan and theUnited States. GCP guidelines include standards on how to design, conduct, record and report clinical trials to ensure protection of participants in trials, in addition to defining the roles and responsibilities of various clinical trial stakeholders.
Human Subjects Research Ethics
Health Information Portability and Accountability Act (HIPAA)
The HIPAA Privacy Rule permits researchers to access, use, or disclose protected health information (PHI) for research purposes when a subject provides formal written authorization. Such use is permissible in accordance with the requirements of the Rule at 45 CFR 164.508. However, there are certain types of research trials that are granted permission by the IRB to waive the requirement of written authorization. The links below contain detailed information regarding the federal regulations and ethical principles.
Essential documents are commonly referred to as regulatory documents. ICH GCP guidance defines essential documents as “those documents which individually and collectively permit evaluation of the conduct of the clinical 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.”
A trial master file or regulatory binder is established at the beginning of any research study and maintained throughout the study. This file aids in the management of the study and is often a piece that is audited by study monitors and FDA officials. Unless otherwise noted, copies of all documents should be placed in the master file at the site and with the study sponsor or Contract Research Organization (CRO).
The following sections outline the required documents according to ICH E6 Guidance for Industry: Good Clinical Practice (GCP). Please note that all human subjects research should adhere to ICH GCPs regardless of the type of clinical study. This information is to provide a knowledge base. You will receive more specific training on this subject later.
- Investigator’s Brochure (IB)
- To document that relevant and current scientific information about the investigational product has been provided to the investigator
- Typically there is a signature page in the IB that should be signed by the Principal Investigator (PI) and returned to the study sponsor
- A copy of the IB signature page should be retained
- When updated IBs are issued, they should be filed accordingly. Outdated IBs should not be removed from the file.
- FDA Form 1572
- To document the agreement of the investigator to provide certain information to the sponsor and to assure that he/she will comply with FDA regulations related to the conduct of a clinical investigation of an investigational drug or biologic.
- Delegation of Responsibilities Log
- To document the investigator’s delegation of certain responsibilities to study personnel in order to conduct the clinical trial.
- Protocol and Amendments
- Typically there is a signature page in the protocol/amendment that should be signed by the Principal Investigator (PI) and returned to the study sponsor
- A copy of the protocol/amendment signature page should be retained
- When amendments are issued, they should be filed accordingly. Outdated protocols should not be removed from the file
- Information Given to a Study Participant
- Informed Consent
- To document the informed consent process
- This document must be approved by the IRB before it can be used
- Other Written Information
- To document that study participants have given their fully informed consent
- Recruitment Advertisement
- To document that recruitment measures are appropriate and not coercive
- This document must be approved by the IRB before it can be used
- Informed Consent
- Financial Disclosure Form (FDF)
- To document the financial agreement between investigator/institution and the trial sponsor
- A FDF must be completed and signed by each member of the trial staff. The original must be returned to the study sponsor and a copy retained
- A new FDF must be completed any time there is a change in any research member’s financial situation (i.e. stock purchases, etc.)
- Clinical Trial Agreement (CTA)
- To document agreements between the PI/institution and the study sponsor and/or CRO
- IRB Approval
- To document that the trial has been subject to IRB review approval.
- Approval will be granted for multiple items, including but not limited to:
- Informed consent document
- Recruitment advertisements and other written information to be provided to the study participant
- IRB Roster
- To document that the IRB is constituted in agreement with Good Clinical Practice
- IRB Correspondence
- To document all correspondence between the study site and IRB.
- This should include all email correspondence.
- Curriculum Vitae (CV)
- To document qualifications and eligibility to conduct trial and/or provide medical supervision of study participants
- Required for each investigator participating in the research study
- CVs must be current and updated every two years, indicate the investigator’s association with the institution where the research study is being conducted, and display the address noted on the 1572 (when applicable)
- Outdated CV’s should not be removed from the file
- Medical Licensure
- To document qualifications and eligibility to conduct trial and/or provide medical supervision of study participants
- Required for each investigator who is a medical doctor participating in the research study
- All licenses must be current
- Expired licenses should not be removed from the file
- Training Records
- To document that study personnel have received adequate study-specific training in order to execute the protocol.
- Training can include a Site Initiation Visit or Investigator Meeting attendance.
- The training record should reflect appropriate training for all study personnel.
- This can include training on specimen collection, handling, and storage.
- Laboratory Certification or Accreditation
- To document competence of facility to perform required tests and to support the reliability of results
- Many sponsors require both CAP and CLIA certification; however, this is very sponsor- and protocol-specific
- Certifications must be current
- Expired certifications should not be removed from the file
- To document normal values and/or ranges of the tests
- Monitor Visit Reports
- To document the completed activities and to address any issues noted during a monitor visit.
- Site Selection Visit (Pre-Trial Monitoring) Report
- Site Initiation Report or Investigator Meeting attendance record
- Monitoring Visit Reports
- Close-out Visit Report
- To document the completed activities and to address any issues noted during a monitor visit.
- Sponsor Correspondence
- To document all correspondence between the study site and sponsor/CRO.
- This should include all email correspondence.
- Miscellaneous Documentation
- Sample of label attached to investigational product containers
- Instructions for handling investigational product and trial-related materials
- Shipping records for investigational products and trial-related materials
- Certificates of analysis of investigational products shipped
- Decoding procedures for blinded trials
- Source Documents
- To document the existence of the subject and substantiate integrity of trial data collected.
- Notification of Serious Adverse Events by Investigator to Sponsor
- Notification by originating investigator to sponsor of Serious Adverse Events and related reports
- Notification of Serious Adverse Events by Sponsor to Regulatory Authorities
- Notification by sponsor and/or investigator to regulatory authorities and IRB of unexpected Serious Adverse Events
- Subject Screening Log
- To document identification of subjects who entered pre-trial screening
- Subject Identification Log
- To document that investigator/institution keeps a confidential list of names of all subjects
- Allows investigator/institution to reveal identity of any subject
- Subject Enrollment Log
- To document chronological enrollment of subjects by trial number
- Signature Sheet
- To document signatures and initials of all personnel participating in the research study
- Investigational Product Accountability Log
- To document that investigational products have been used according to the protocol
- Documentation of Investigational Drug Destruction
- To document destruction of unused investigational products by sponsor or at site
Data Safety Monitoring Plans (DSMP)
Data Safety Monitoring Board or Committee (DSMB or DSMC), is a group of individuals with clinical expertise in the areas of the diseases or treatments administered as part of a research study. Often these committees also include biostatisticians, clinical research experts and research ethicists. This committee functions as an independent group tasked with the responsibility to continually review the safety of the research study. Through this review, they also assess the scientific integrity and validity of the research study. This group can make recommendations on the conduct of the study to the IRB, Investigator and Sponsor.
The level and frequency of review should correlate to the level of risk involved with the research study. Per FDA guidelines, a formal DSMC/ DSMB should be established for studies where mortality and morbidity are primary data endpoints. For multi-center cooperative group and industry sponsored research studies, the sponsor is responsible for creating an independent DSMC/DSMB. For trials of lower risk to participants, the Data and Safety Monitoring Plan (DSMP) may only require the Principal Investigator (PI) at the site to monitor the safety and scientific validity of the study at regular intervals.
- Center for Clinical and Translational Regulatory Knowledge: DSMP
- NIH: Guidelines for Data and Safety Monitoring
- NCI: Guidelines for Data and Safety Monitoring
- FDA: Establishment and Operation of Clinical Trial Data Monitoring Committees
Subject Management & Site Activities
Site Monitor Visits
Study sites are monitored to ensure oversight of the clinical research study by the sponsor. Regular site monitor visits can be broken down into four types: pre-study visits, initiation visits, periodic monitoring visits, and close-out visits. Study sites may also be monitored or audited by the FDA, Clinical Research Organizations (CROs), IRBs and sponsors.
Pre-study visits site selection visits (PSSVs) are conducted to determine if the investigator and clinical site have the capability to conduct the study. During this visit, both an investigator and a study coordinator must be available. When applicable, pharmacy staff may also need to be available. The monitor will usually request a tour of the facility and time to discuss the basic fundamentals of the protocol and how that relates to the feasibility of recruiting potential participants.
Other topics of discussion during the pre-study visit include:
- Investigator responsibilities
- Qualifications of investigator or other site personnel
- Study objectives, protocol-required procedures, eligibility criteria, and patient recruitment
- IRB (e.g., informed consent requirements)
- Adverse event reporting, source documentation, and record retention
- Space requirements, availability of a secure area to store investigations drug or devices, availability of required equipment
A Site Initiation Visit (SIV) is when the research study team receives adequate training from the sponsor or CRO on the protocol. It is also the opportunity for the sponsor or CRO to ensure that the investigator fully understands his/her responsibilities (21 CFR 312 Subpart D). This visit usually occurs after the site has completed all regulatory requirements and has obtained IRB approval for the research study at their site. The initiation visit is the last step before the study site is activated for enrollment by the sponsor.
During study start-up, a sponsor may choose to hold an investigator meeting for a large number of sites in lieu of conducting many site initiation visits. It is the decision of the P.I. who attends this meeting.
Other topics of discussion during the site initiation visit include:
- Study overview, eligibility criteria, procedures, access to suitable patient population
- Lab manual, requirements for research sample processing and shipping
- Regulations and Good Clinical Practice (GCP) guidelines, informed consent requirements, IRB obligations, adverse event reporting, drug accountability
- Data forms review including Case Report Forms (CRFs)
- Regulatory documents and study file organization
- 21 CFR 312 Subpart D Responsibilities of Sponsors and Investigators
Periodic Monitoring Visits
The sponsor and/or CRO will develop a monitor plan that includes the frequency and duration of periodic monitor visits. The focus of these visits is to evaluate the way the study is being conducted and to perform source document verification. These visits can occur every few weeks to once a year and can take less than one day up to several days at a time. It is important to be familiar with the contract agreements, as they may contain the agreement as to the frequency and duration of site monitoring visits and the sponsor’s data entry expectations. The contract agreement should match what the sponsor and/or CRO creates in the site monitor plan.
Preparing for a periodic monitoring visit:
- Identify a quiet place for the monitor to work and ensure access to a copy machine, phone, water fountain, and restroom
- Complete all necessary CRFs
- Confirm that Serious Adverse Event (SAE) forms have been submitted and are available for review
- Obtain medical records for the CRFs to be reviewed
- Organize study file documents for review
- Confirm that signed consent forms for all enrolled participants are available
- Schedule an appointment for the monitor to visit the pharmacy if needed
- Schedule time for the study coordinator to meet with the monitor towards the end of the visit to review findings
- Schedule time for the investigator to meet with the monitor towards the end of the visit to review findings
When the research study has been completed at a site, a close-out visit occurs. This type of visit can take the form of an on-site visit or, in some cases, be conducted via a telephone call. Some close-out visits are also combined with a final periodic monitoring visit.
Action items during the close-out visit may include:
- Discuss timelines and strategies for the completion of outstanding case report forms and queries
- Return or destruction of study drug
- Collect outstanding patient data forms and study forms such as the screening and monitoring logs
- Perform a final review of the study file documents
- Discuss the plans for record retention
- Discuss ongoing investigator responsibilities
Drug Supply Management and Accountability
The record keeping associated with the receipt, storage, and dispensation of an investigational product is known as study drug accountability. While the study sponsor is responsible with packaging and distributing the product to the study sites, it is the responsibility of the site to maintain adequate records of the products handling and dispensation.
Often sponsors will provide tools such as tracking logs to assist in the maintenance of such records. However, if no tools are offered by the sponsor, the site should plan to develop their own tracking method.
Study drug will be packaged to protect the product, ease dispensation, and to preserve blinding when necessary. Typically the packaging will offer a place to record the study participant ID.
When study drug is received at the study site, it is important to inspect the shipment in its entirety. The packing slip should be compared to both the order form and the contents of the shipment. Often study sponsors will require that the packing slip be signed, dated, and returned in order to acknowledge receipt of the shipment. If it appears that the shipment is incomplete or was damaged in transit, contact the sponsor immediately.
Storage instructions should be included with the shipment, including specifications for temperature ranges. Study drug should always be stored in a secure location, either at the study pharmacy or in a locked cabinet within a separately locked room. Temperature logs are maintained to ensure that the product remains viable.
If study drug requires storage in a refrigerator, the refrigerator will have a lock on it and will remain free of food. This means that study drug cannot be kept in the break room refrigerator. Likewise, lunch cannot be kept in the study drug refrigerator.
The tracking of study drug dispensation can become complicated with many study participants over the course of a lengthy trial. Meticulous records are required in order to be compliant with accountability. Study drug received from the sponsor will be tracked, as well as drug dispensed to study participants. So there is a constant flow of drug in and drug out.
Study drug received is tracked on the same log as study drug dispensed.
|Date||Participant ID||Lot#||Quantity||Total Remaining|
|Received||06/01/2010||NA||L0124||12 bottles||12 bottles|
|Dispensed||06/03/2010||101||L0124||2 bottles||10 bottles|
|Dispensed||06/04/2010||102||L0124||1 bottle||9 bottles|
|Dispensed||06/06/2010||103||L0124||2 bottles||7 bottles|
|Received||06/07/2010||NA||L0216||12 bottles||19 bottles|
|Dispensed||06/10/2010||101||L0124||1 bottle||18 bottles|
Study drug received is tracked on one log and study drug dispensed is tracked on a separate log.
|Received||06/01/2010||NA||L0124||12 bottles||12 bottles|
|Dispensed||06/03/2010||101||L0124||2 bottles||2 bottles|
|Dispensed||06/04/2010||102||L0124||1 bottle||3 bottles|
|Dispensed||06/06/2010||103||L0124||2 bottles||5 bottles|
|Dispensed||06/10/2010||101||L0124||1 bottle||6 bottles|
Study drug received is tracked on one log and study drug dispensed is tracked on a separate log per subject.
|Received||06/01/2010||NA||L0124||12 bottles||12 bottles|
|Received||06/07/2010||NA||L0216||12 bottles||24 bottles|
|Dispensed||06/03/2010||101||L0124||2 bottles||2 bottles|
|Dispensed||06/10/2010||101||L0124||1 bottle||3 bottles|
In rare cases, the unblinding of study drug is required. This may occur as a result of an adverse event where it is necessary to know the type of study treatment that was being received in order to determine how to treat the event. Unblinding procedures vary from study to study and should be covered during protocol training, such as the Site Initiation Visit or Investigator Meeting.
The sponsor will determine if remaining study drug will be returned or destroyed on site at study completion. Thus drug reconciliation often occurs as part of the Close-Out Visit. It is important to keep all empty containers until a reconciliation has occurred and permission was granted by the sponsor to return or destroy drug. This includes keeping any empty pill bottles, vials, etc. Study participants should always be informed that they should return their empty containers rather than discarding them. Adequate records should be maintained whether study drug is returned or destroyed on site. Any discrepancies should be clearly noted in a memo-to-file.
Recruitment of Research Study Participants
Scientific progress depends on successful recruitment and retention of participants in research studies. Often the most difficult and challenging aspect of conducting research studies can be the execution of efficient and effective recruitment and retention strategies of research study participants. Implementing these strategies can dramatically contribute to increased workload and complexity of managing research studies, but can be pivotal to the success of achieving key research objectives.
Recruiting is the responsibility of the entire research staff. Often, advertising is used and must be Sponsor and IRB approved beforehand. Types of advertising include radio, TV, newsprint, internet, direct mailings and Dr. to patient letters. Advertising can be done at the site level. This means that the research staff is responsible for creating the ads and submitting them for approval by the sponsor and the IRB. However, there are instances when the Sponsor chooses to run a central ad campaign for the study. A central ad campaign can include any of the forms of advertising listed above but is created and initiated by the Sponsor.
Informed Consent in Research
Obtaining informed consent for a research study requires open and honest communication between the researcher and the study participant. Much attention has been given to the consent document readability and its comprehension. However, it is important to remember that the document is a proxy and reference for a conversation. The conversation should be based upon the key elements of the consent document which include but are not limited to; the study objectives, procedures, duration, risks, benefits, alternative options, confidentiality of records, contact information for any participant questions, compensation if applicable, additional costs and compensation for research injury if applicable. It is essential that participants understand that participating in a research study is completely voluntary; they can withdraw from the study at any time or choose not to participate.
Informed consent should be obtained after the participant has been presented with pertinent information, has had adequate time to review the consent document and have all questions answered. Consent should also be obtained prior to any study specific procedures. Participant privacy during the discussion is paramount and the environment should be free of undue influence and coercion from the research team.
It is important to note that informed consent is a continuous dialogue with the participant which reinforces the key elements of initial consent throughout the duration of the study. New adverse events or important findings that may increase a participant’s risks or willingness to continue in the research study should be disclosed to the participants and to the IRB.
- FDA: A guide to Informed Consent
- 45 CFR 46: 41.116 General Requirements of Informed Consent
- FDA: 21 CFR 50
- ICH E6 Good Clinical Practice
- FDA : IDE Informed Consent
Special Consent Considerations
Clinical research studies that involve children, non-English speaking individuals or the use of a Legally Authorized Representative (LAR) have additional guidances, regulations and processes that may apply.
- Assent and Parental Permission
- Emergency Research
- Short Form Informed Consent
- Research Involving Pregnant Women, Fetuses, or Neonates
- Research Involving Prisoners
- Research Involving Children
- Vulnerable Populations: Students, Employees, and Adults Unable to Provide Consent
Documenting the Consent Process
It is important to document the consent process at the time the informed consent form is signed by the study participant or legally authorized representative. The source document should state the date, participant name, medical record number, study number and study title. It should state the key elements of the consent that were discussed with the potential participant and any further details of the discussion that are pertinent to the subject’s understanding of the study or information that could impact their decision to participate in the study. It should state that the participant had adequate time to review all information and voluntarily signed the informed consent form(s) with an understanding that they are able to withdraw from the study at any time without penalty. It should also state the participant received a copy of all forms signed and that the participant signed and dated the consent form prior to any research specific tests. It is essential that the forms are completed appropriately, without errors and omissions of signatures, printed names, initials and dates.
Informed Consent and Assent
Federal regulations require investigators to: ensure that potential participants clearly understand the risks and benefits associated with the research before enrollment, provide potential participants with all information necessary to decide whether or not to participate in the research, and most importantly, protect the rights, safety, and welfare of all research participants under their care. One of the three ethical principles outlined in the Belmont Report is “Respect for Persons” and this principle is applied to research with human participants in the form of informed consent. Informed consent is the process of information exchange between the participant and the investigator (or designee), beginning with initial contact and continuing throughout the study, to ensure that the participant can freely decide whether or not to participate in research.
Informed consent is an essential part of ethical research involving human participants. Institutional Review Boards (IRB) and investigators are responsible for ensuring that research involving participants provide informed consent prior to participating in research, unless the requirement for informed consent is waived or altered (in non-exempt research) by the IRB.
Assent and parental (or guardian) permission must be obtained as required by federal regulations and IRB determinations for research involving children. Assent is generally required for children based on their ages, maturity, condition, and the nature of the research, unless assent can be appropriately waived or some or all of the children are not capable of providing assent.
Assent may also be appropriate for adults with diminished decision-making capacity and other adults unable to consent for themselves, for whom a legally authorized representative will provide informed consent.
Basic Elements of Informed Consent (45 CFR 46.116(a)(b) and 21 CFR 50.25(a)(b))
The consent process must include the following basic elements:
- A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the participant’s participation, a description of the procedures to be followed, and identification of any procedures which are experimental;
- A description of any reasonably foreseeable risks or discomforts to the participant;
- A description of any benefits to the participant or to others which may reasonably be expected from the research;
- A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the participant;
- A statement describing the extent, if any, to which confidentiality of records identifying the participant will be maintained, and when applicable, that notes the possibility that the Food and Drug Administration may inspect the records;
- For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained;
- An explanation of whom to contact for answers to pertinent questions about the research and research participants’ rights, and whom to contact in the event of a research-related injury to the participant; and
- A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the participant is otherwise entitled, and the participant may discontinue participation at any time without penalty or loss of benefits to which the participant is otherwise entitled.
When appropriate, one or more of the following elements will also be provided to potential participants during the consent process:
- A statement that the particular treatment or procedure may involve risks to the participant (or to the embryo or fetus, if the participant is or may become pregnant) which are currently unforeseeable;
- Anticipated circumstances under which the participant’s participation may be terminated by the investigator without regard to the participant’s consent;
- Any additional costs to the participant that may result from participation in the research;
- The consequences of a participant’s decision to withdraw from the research and procedures for orderly termination of participation by the participant;
- A statement that significant new findings developed during the course of the research which may relate to the participant’s willingness to continue participation will be provided to the participant; and
- The approximate number of participants involved in the study.
NOTE: Any informed consent, whether written or oral, must not include exculpatory language such that the participant is made to waive, or appear to waive, any of his or her legal rights or to release the institution or its agents, the investigators, or sponsor from liability for negligence.
Waiver of Documentation of Informed Consent
An IRB may waive the requirement for the investigator to obtain a signed consent form for some or all participants if it finds either:
- That the only record linking the participant and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality. Each participant will be asked whether the participant wants documentation linking the participant with the research, and the participant’s wishes will govern; or
- That the research presents no more than minimal risk of harm to participants and involves no procedures for which written consent is normally required outside of the research context.
Waiver or Alteration of Consent Process
An IRB may approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent set forth in this section, or waive the requirements to obtain informed consent provided the IRB finds and documents that:
- The research involves no more than minimal risk to the participants;
- The waiver or alteration will not adversely affect the rights and welfare of the participants;
- The research could not practicably be carried out without the waiver or alteration; and
- Whenever appropriate, the participants will be provided with additional pertinent information after participation.
Screening potential participants is essential to the successful recruitment to a research study. This is the process by which the research team determines whether an individual may be an appropriate candidate for the study.
The participant is required to sign the HIPAA Authorization form at the time of signing the informed consent. It is important to note that the consent must be signed prior to the initiation of any research specific testing/procedure or completion of study specific questionnaires that may qualify as participation in the research study. In other words, informed consent must be obtained before anything is done to a potential participant that is not deemed standard of care for the patient diagnosis and only done for the purposes of determining patient eligibility for enrollment in the research study.
The Privacy Rule allows activities “prepatory to research”. The rule allows research teams to identify the feasibility of conducting a specific research study. This is merely an exploratory process and does not allow the collection of PHI or allow the research teams to actively identify and recruit individuals for a study.
Participants enrolled in a research study should represent the selected patient population identified for analysis. Each research protocol should include defined inclusion and exclusion criteria to allow clear identification of appropriate study participants. The study team should be well acquainted with the details and requirements of eligibility for their research study. Eligibility criteria must be strictly followed to ensure that ineligible participants are not enrolled and exposed to unnecessary risk and so that the final data points can be analyzed without compounding variables. All information provided by the potential participant and source documents must be reviewed to identify all important elements that may or may not make the patient eligible for the research study.
Enrolling ineligible subjects is considered to be a compliance violation of the currently approved IRB protocol (investigational plan), GCP guidance, federal regulations, and the Statement of the Investigator (FDA Form 1572). If specific eligibility criteria are negatively impacting recruitment and enrollment of participants, it is recommended that the study team evaluate the possibility of amending the protocol to allow for more flexible eligibility criteria. Accepting waivers for eligibility from sponsors for anything other than eliminating the apparent and immediate hazard to research participants is also considered to be a compliance violation.
It is helpful to have at least two members of the research team review and confirm eligibility of the participant to reduce the chances of accidentally enrolling an ineligible participant.
A screening log is a helpful tool that the research team can utilize to track why individuals are not eligible for a research study. It allows for easy identification of the specific criteria that may be negatively impacting participant enrollment. Many sponsors require a site to maintain a screening log. It is important to note that unless an individual signs the consent and HIPAA Waiver of Authorization, the potential participant information must be de-identified.
Scheduling and Preparing for a Study Visit
All protocols require participants to be scheduled for specific research visits. The number and length of time required for a research appointment to occur is dependent on the specifics of the study design. The specifics of the appointment are dependent on the location of the appointment. Appointments can occur in outpatient clinics, diagnostic testing locations as well as the research site.
It is important to set the expectations of each visit for the participant. For example, where the visit will take place, how long the visit will take, tasks to be completed at the visit, special instructions the participant must follow prior to the visit, directions and parking information, whether or not compensation for time or parking will take place and who will be involved in the visit. This information is located in the Informed Consent Form and should be reviewed with the patient when scheduling appointments.
Once the visit is scheduled, follow-up contact in the form of a phone call to the participant can reinforce the requirements of the study and further explain important details of the upcoming visit. It is important to be understanding of the participant’s personal schedule and to help identify research visit times that are convenient for the individual to commit to without sacrificing protocol compliance.
Prior to each study visit, the research team must be prepared for all known and unknown tasks that may need to be completed per protocol. If applicable, research lab kits should be prepared and available to the appropriate clinical team drawing the samples; participant questionnaires should be prepared; flowsheets required for research documentation should be made available to the appropriate team members; and any end of study visit items should be readily available if the participant decides to withdraw from the study or is removed from the study due to adverse events or investigator discretion, etc.
Obtaining a Subject ID Number
A subject ID Number needs to be assigned to a research participant. When first scheduling the participant, research staff can check whether a subset of numbers has been given to the site or if they have to obtain this number through an IVRS system.
Many studies require procedures that must take place in a location that is specifically equipped (i.e., a radiology facility will do x-rays) to do so. These visits will be arranged by the key research staff involved in the research visit in accordance to any subcontracts or verbal agreements made with the off-site facility(s).
When scheduling a participant for an on-site or an off-site visit, it is important to ensure that the visit is being scheduled within the allowed time period (in window) and that all of the demographic and contact information is complete and accurate in the site’s records so that there is no breach in communication should the appointment need to be rescheduled by the site.
Data Management (CRFs and Source)
Study visits and procedures are structured in accordance with the study protocol to collect specific data points. Prior to each study visit it is important to review the research protocol to identify all of the scheduled visits and procedures to be completed. This will help ensure that the site is prepared for each study visit and will have the necessary staff, equipment and supplies available.
During each subject study visit, the research team will document the details of the tasks or procedures completed and any other pertinent research information in a source document. Utilization of a source document will help ensure protocol and regulatory compliance. Source documents are the original records of participant information. Please note that any form of documentation can be used as a source document and is subject to review when validating the integrity of data collection and analysis. Common source documents are participant medical records, phone encounters or notes, lab and diagnostic test results, participant diaries and specific research worksheets used to document key research data elements.
Case Report/Record Forms (CRFs)
Most industry sponsored trials will provide paper Case Record Forms /Case Report Forms (CRFs) or access to Electronic Case Report Forms (eCRFs). The CRFs identify all of the data elements required by the sponsor and should correlate with the required data elements outlined in the protocol. Study site staff transcribes information from relevant source documents to the CRFs or eCRFs.
- All paper entries should be completed legibly, preferably in black ink
- The Principal Investigator (PI) or their designee(s) may enter data on the CRFs and make corrections to the original CRFs as long as they are listed on the Authorized Representative Signature Record (Site Signature Log).
- Only acceptable medical terminology and approved institution abbreviations should be used.
- Avoid leaving blank data fields, using question marks, and using zeros as a response on CRFs.
The Clinical Research Director will often review the source documents and CRFs for legibility, completeness and consistency. Any data that is missing or errors identified by the Clinical Research Director will need to be resolved. This will be completed before the data can be reviewed by the Contract Research Organization (CRO) or Sponsor. Studies may use eCRFs with data verifiers that screen all data fields and generate queries that are sent to the study center requesting corrections to the primary study document and electronic correction in the data base. The explanation of missing data or data irregularities, including deviations from study protocol may require an explanation in the form of a memo/note to file. The Clinical Research Director will review the eCRFs to insure their completeness and accuracy periodically and any queries will be answered according to the CTAs requirements.
Corrections to any source document, CRFs and related study documents should be done using the following guidelines:
- A single line through the original data error, which will allow the data to remain legible (DO NOT erase, write over or use whiteout)
- The data corrections should be documented in ink, initialed and dated by the researcher completing the correction.
Requesting Medical Records
- The study protocol will indicate when medical record information is necessary to meet the study requirements. Medical record information can be obtained by requesting a general medical release form to be signed by a study participant from whom the information belongs.
Maintenance and Storage of Research Records
Research records should be stored according to IRB requirements for at least three years after the completion of the research study or longer if required by the sponsor. FDA regulations state that study records must be stored for at least two years past the date of approval of a New Drug Application (NDA) or discontinuation of the research study if a NDA will not be submitted by the sponsor. Please refer to our SOPs for our current procedure.
Adverse Events and Serious Adverse Event Management
Regular reporting of adverse events is done through data collection in source documents and case report forms. These adverse events are already known as potential risks when participating in a research study with a specific investigational product. At the time a participant begins a research study, it is important to have a documented baseline assessment that is detailed with health history and current health issues prior to exposure to the investigational product. As the participant is exposed to the investigational product, the research team must document any changes in health that may be due to the research study product and report these adverse events through normal data collection tools provided by the sponsor.
Research studies involving interventions such as drugs, biologics or devices require the investigators and sponsors to appropriately report any serious adverse events (SAEs) observed in human participants that are considered serious, unexpected and related to the investigational product as defined by federal regulations. These unanticipated problems need to be reported promptly to the IRB, sponsor and federal agency because they may involve greater risks to human subjects or others than previously expected. Each entity has defined reporting requirements for serious adverse events. It is important to note that sometimes the event is required to be reported to the sponsor as an SAE but it may not need to be reported to the IRB. The research team must be familiar with the various reporting definitions, requirements, and timelines that the reports must be completed. It is important to document when the research team is informed of a potential SAE. This is the point when the timeline for submitting the required reports begins. Sometimes only minimal information is known at the time the initial reports are due; additional information can be submitted once it is available as an amendment to the initial report.
Most reports require a brief history of the event. This description should be professionally written and presented factually. Key information that is helpful to the reviewers of the reports are: participant demographic information, when the participant started the research study, what research intervention the participant was receiving, previous medical history, concomitant medications, last exposure to investigational product, abnormal labs or diagnostic tests, when the study team was notified of the event, description of the actual event, relationship of the AE to the investigational product, whether the participant was hospitalized, if the event has resolved or not, and whether the participant will be removed from the research study or continue to receive the research product.
Study Implementation/ In-Service Training
After a study receives IRB approval, it is important to have 2 formal study implementation meetings with all research staff. The focus of the 1st implementation meeting is to ensure that all questions regarding the protocol be addressed and that they are taken to the Investigator Meeting and resolved if possible. This is also the time to discuss patient recruitment strategies. The focus of the 2nd implementation meeting (post investigator meeting) is to ensure that protocol-specific issues have been resolved prior to opening a study to participant recruiting. This is also the opportunity to ensure that all key personnel have completed any protocol specific training and are familiar with the expectations of the protocol and investigator responsibilities and the delegation of responsibilities.
The implementation meetings are detailed planning session involving the key personnel associated with the study. It is mandatory for all research staff to attend these meetings.
The agenda may include, but is not limited to, the items below:
- Key study personnel with contact information
- Study overview including objectives, design and purpose
- Participant eligibility and registration requirements
- Study specific tasks to be completed with timeline, feasibility and logistical requirements
- Investigational product management, storage, ordering and shipping requirements
- Required source documentation and examples of documentation tools
- Specific staff requirements
- Data elements collected and timeline requirements for data submission
- SAE reporting guidelines
- Other processes or procedures that must be defined and implemented prior to enrolling study participants.
- FDA:21 CFR 312.60: Investigator Responsibilities http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.60
Specimen Collection, Handling, and Storing
Specimen collection for research protocols requires specific attention to the proper timing, collection, labeling, processing, storage, and shipping of samples. Prior to the start of specimen collection, the research coordinator needs to gather information and understand the proper procedure for each of the samples being collected.
Most protocols will have the details of how to collect, process, and store research samples. Typically, the lab handling the assay will have specific instructions on how to handle the specimen from collection to storage including what identifiers are necessary for the storage labels. Timing for the collection of research samples is extremely important to ensure quality data. Samples being collected for research that are timed based on medication dosages such as Pharmacokinetics (PK) samples need to be collected exactly on time. If the collection time is incorrect, the specific time collected needs to be noted so that the sample results can be correlated with that time.
Other general knowledge of the different types of specimens and handling of specimens can be helpful. General knowledge may include which additives are in different types of tubes, whether collection tube requires mixing or inversion and suggested number of inversions per collection tube, differences between serum, plasma, cells, whole blood, type of tube required for each sample, length of time the sample is stable, specific centrifugation information such as centrifugation speed (Revolutions Per Minute, RPMs) and length of time required for proper separation of the sample for the required assay. Some specimens require the use of a refrigerated centrifuge, specific ultra-low freezers (-20 or -70 degrees) or room temperature storage. Other special considerations could include light or temperature sensitivity from collection to storage which may require foil wrapped collection tubes and amber storage tubes or ambient (room temperature) collection until being assayed. It is important to note that every test can vary depending on the type of machine being used to assay the sample so communication with the involved assay lab is important.
International Air and Transportation Association (IATA) training and proof of IATA training are required by law for any person who is responsible for shipping dangerous goods via a public delivery service. All Beyer Research staff memebers are required to complete this training, keep documentation on file and renew their certification every three years. Your trainer will give you more information regarding this training.
Training for Clinical Skills
- When clinical skills are required to complete research studies, training is available for basic skills. Training is offered for EKGs, vital signs, and phlebotomy.
Standard Operating Procedures (SOPs)
Standard Operating Procedures (SOPs) are standardized written procedures, with detailed instructions to record routine operations, processes and procedures followed within a business organization.
In clinical research, SOPs help define the group’s (e.g., unit, division, department, institution, etc…) standard practices and daily processes conducted to assure execution of research tasks in accordance with institutional, state and federal guidances.
Beyer Research’s SOPs contain enough detail to guide research staff through a particular procedure and thereby establish uniformity in the everyday functions of the department. The SOPs have a specific aim and are written in a general format to allow for easy implementation across a broad set of venues and circumstances. The SOPs must be followed without deviation.
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