GOOD CLINICAL PRACTICES GCP TRAINING Dental Research Administration

GOOD CLINICAL PRACTICES (GCP) TRAINING Dental Research Administration Version 10. 4. 17

Definitions • Good Clinical Practice (GCP)- An international ethical and scientific quality standard for designing, conducting, recording, and reporting for clinical trials. • Investigator- A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator (PI). • Sub-investigator- Any study team member that is designated and supervised by the PI to perform trialrelated procedures and/or make important trial-related decisions • Sponsor- An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of clinical trial.

Definitions • Institutional Review Board (IRB)- An independent body consisting of medical, scientific and non-scientific members, that is responsible for ensuring the protection of the rights, safety and well-being of human research participants, by reviewing, approving and providing continuing review of the trial protocol, amendment, and methods/materials used to obtain/document informed consent. • Independent Ethics Committee (IEC)- An independent body consisting of medical and non-medical members, that is responsible for ensuring the protections of the rights, safety and well-being of human subjects involved in a trial by reviewing and approving/providing favourable opinion on, the trial protocol, suitability of investigators, facilities, and methods/materials to be used to obtain/document consent. (ex-U. S. )

GCP Overview • In the early 1990’s, the European Union, Japan, and the U. S formed the International Conference on Harmonisation (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use to standardize guidelines and requirements for drug marketing registrations. • This resulted in ICH E 6 Good Clinical Practice (GCP)- the current international ethical and scientific quality standard for designing, conducting, recording, and reporting of clinical research. • Following GCP standards ensures the protection of research participants and the integrity of data collection.

GCP Training Requirements • All personnel involved in the conduct or oversight of a clinical study are required to complete GCP training. • A clinical study is any research study in which human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. • GCP Training is not protocol specific; the ICH GCP Principles apply to any type of clinical trial. • GCP Training must be refreshed every 3 years to be consistent with current guidelines.

Principles of ICH GCP There are 13 ICH GCP Principles: • 1) Clinical trials should be conducted in accordance with the ethical principles • 2) Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit to the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risk. • 3) The rights, safety and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. • 4) The available non-clinical and clinical information on an investigational product should be adequate to support the proposed clinical trial. • 5) Clinical trials should be scientifically sound and described in a clear, detailed protocol. • 6) A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favorable opinion. that have their origin in the Declaration of Helsinki and that are consistent with GCP and the applicable regulatory documents

Principles of ICH GCP • 7) The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist. • 8) Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s). • 9) Freely given informed consent should be obtained from every subject prior to clinical trial participation. • 10) All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification. • 11) The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). • 12) Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol. • 13) Systems with procedures that assure the quality of every aspect of the trial should be implemented.

INFORMED CONSENT OF RESEARCH PARTICIPANTS

What is Informed Consent? • Informed consent is more than just a signature on a form. It is a process of information exchange that may include, in addition to reading and signing the informed consent document, subject recruitment materials, verbal instructions, question/answer sessions, and measures of subject understanding. • The consent document will contain all the information about risks, benefits, and requirements for participation that a potential subject will need to make an informed decision about participating in the study. All elements from ICH 4. 8. 10 must be included. • The consent document, along with any other written information to be provided to subjects must be approved by the IRB/IEC prior to use • Consent must be obtained/signed PRIOR to a subject’s participation in a trial (before any study procedures are performed)

The Process of Informed Consent • Subjects should have ample time to review the Informed Consent Form (ICF) and to ask questions and receive answers before a decision is made and subjects should not be unduly influenced to participate • ICF should be signed and personally dated by the subject and/or their legal representative (when applicable) and the person who conducted the consent • A signed and dated copy of the ICF should be given to the subject or their legal representative • The informed consent process should be documented in the CRFs. If consent is obtained the same day that study involvement begins, CRFs should document that consent was obtained prior to participation in the research

The Process of Informed Consent • Although a participant must sign the informed consent document before they can participate, it is important make participant’s aware that they can withdraw their consent to participate at any time during the study • Subjects should not be asked to waive legal rights or release investigator or sponsor from liability for negligence • Subjects should not be unduly influenced to participate • The language used in oral and written information should be understandable to the subject or their legal representative and impartial witness (when applicable) • Please see http: //viceprovost. tufts. edu/HSCIRB/policiesregulations/short-form-policy/ for further details regarding enrolling Non-English speaking subjects • The ICF must be updated and IRB-approved when new information is available that may be relevant to a subject’s consent to participate

The Process of Informed Consent The site investigator or their delegate should sit with the patient to discuss the details of the study. • • • “This is the study we are conducting” “These are the benefits of participating” “These are the possible risks” “As a study participant, these are the commitments you are expected to fulfill” “Do you have any questions? ” • Have subject sign and date the consent form • The responsible party for the site signs and dates the consent form. • Make a copy of the signed document for the patient and retain the original with the patient’s study file. • Only BLACK INK should be used on the ICF

Vulnerable Populations Vulnerable subjects are individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. This may include: • • Dental or medical students, employees Patients with incurable diseases Pregnant women, fetuses, and neonates Prisoners Children Individuals incapable of providing informed consent

Vulnerable Populations • When a subject (eg. Minor, incapacitated) can only be enrolled with the consent of a legal representative, the subject must be informed to the level of their understanding, provide assent (when possible) and personally sign and date the consent form. • In emergency situations where the subject and legal representative are unable to consent, enrollment requires protective measures to be described in protocol or other IRB/IEC approved documents. Subject or their legal representative should be informed as soon as possible and consent to continue and other consent as appropriate • If the subject/legal representative are unable to read, an impartial witness must be present during the consent discussion and sign and date the ICF

Errors in the Consent Process • Errors are considered protocol violations and must be reported to Tufts Dental Research Administration who will then report to the IRB. • Examples of Consent Errors: • • • Out of date version of consent was used (check the IRB approval stamp to make sure it is current) Participant signed consent AFTER study procedures were performed Missing information on signed consent (e. g. initials, date, witness signature) Corrections made inappropriately Subject not dating consent themselves (note: investigator cannot date for participant) Pre-signing consent forms (not allowed, must be signed at same time as participant).

INVESTIGATOR QUALIFICATIONS AND AGREEMENTS

Investigator Responsibilities- Overview • Demonstrates evidence of adequate training, education and experience (as shown on up-to-date CV) • Be aware of and comply with GCP and regulatory requirements • Be familiar with and responsible for Investigational Product • Document delegation of duties to appropriately qualified staff • Use of qualified support staff • Allow for monitoring, auditing, and inspection of study documents to enable sponsor and regulatory oversight Monitoring- sponsor oversight of the trial to ensure it is conducted according to protocol, GCP, SOP and regulatory requirements • Auditing- systematic and independent examination of trial-related activities • Inspection- official review of documents, facilities, records, and any other resources by regulatory agencies •

Adequate Resources • Have the potential to recruit suitable subjects (access to the patient population) • Have adequate time to conduct the trial • Have sufficient qualified staff and facilities to conduct the trial • Ensure staff are adequately informed about study protocol, IP and all tasks related to the protocol • Supervise delegated tasks, ensuring qualification of delegates and implementing procedures to ensure integrity of output

Medical Care of Trial Subjects • A qualified physician or dentist who is an investigator or subinvestigator should be responsible for all trial related medical decisions • It is the responsibility of the PI/institution to ensure appropriate medical care for Adverse Events (AEs) and clinically significant lab deviations related to the trial, and inform subjects if medical care is needed for intercurrent illness • Inform the subject’s primary care physician of their participation in the trial, upon receiving permission from the subject (without their permission, this would be a breach of confidentiality) • The investigator should make a reasonable effort to determine the reason for a subject’s premature withdrawal from the trial

Communication with the IRB/IEC • Before a trial can begin, written, dated approval/favourable opinion for the protocol and all study documents to be provided to subject (e. g. , ICF, advertisements) must be obtained from the IRB/IEC • A copy of the Investigator’s Brochure (IB) and updated IB must be provided to the IRB/IED • Before and during the trial, must provide all documents required by IRB/IEC for review and appropriate approval/favourable opinion • Any modifications to approved research, including modifications to the informed consent process and document, must be approved by the IRB/IEC prior to use Per federal regulations, an IRB must conduct continuing review of previously approved research at intervals appropriate to the degree of risk, but not less than once per year, in order to review: • • • Risk assessment and monitoring; Adequacy of the process for obtaining informed consent; Local issues/Investigator and institutional issues; and Research progress

Compliance with Protocol • Trials must be conducted according to the approved protocol, GCP and applicable regulatory documents (e. g. , sufficient documentation to support subject meeting inc/exc criteria) • The acceptance to follow the protocol is documented in a protocol signature page or contract • No protocol deviations or changes prior to sponsor and IRB approval should occur • Exception- if deviation is necessary to eliminate immediate hazard to the trial subject Deviations must be documented and rationale provided to the sponsor, IRB and other applicable regulatory authorities • • Exception- If changes are minor logistical or administrative (e. g. contract details) then deviations are documented and explained

Investigational Product (IP) • The PI is responsible for IP accountability, delegation of activities, and supervision of an appropriately qualified person • Documentation must be maintained regarding delivery, inventory, dispensation, usage, disposal or return and reconciliation of all IP and other study medication • IP must be stored per requirements • IP must be used per the approved protocol • The correct use of the IP must be explained to subjects, and understanding/compliance must be periodically checked

Randomization Procedures and Unblinding • Blinding is a procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). • The investigator should follow the trial’s randomization procedures (per the approved protocol) • IP should be coded and labeled in a manner that protects the blinding, if applicable. • The code should only be broken in accordance with the protocol For blinded trials, any premature unblinding must be promptly documented and reported to the sponsor • • e. g. , accidental unblinding, unblinding due to a serious adverse event

Premature Termination or Suspension of Trial If a trial is prematurely terminated or suspended for any reason, the PI/institution should: • promptly inform the trial subjects • assure appropriate therapy and follow-up for the subjects, and, • inform the regulatory authority(ies), where required by the applicable regulatory requirement(s) • • It is the responsibility of the PI to communicate study termination or suspension to the sponsor, IRB and institution as applicable, including a detailed written explanation

PARTICIPANT SAFETY AND REPORTING

Adverse Events (AEs) • An Adverse Event is any unwanted medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. • An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product • Examples include: A physical event such as a rash or broken bone • A psychological event such as a bout with depression • A laboratory event such as an elevated blood pressure or a positive test for Candidiasis • An increase in the severity or frequency of a pre-existing condition (an infection in a pre-existing wound) •

Adverse Drug Reactions (ADRs) For new investigational medical products, or products being investigated for new uses, particularly as therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions • • “Responses to a medicinal product” means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i. e. the relationship cannot be ruled out. • For marketed medical products, an ADR is a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function • An ADR is not the same as an AE- an ADR is the result of the use of medicine or treatment • • All ADRs are AEs, but only some AEs will be ADRs An unexpected ADR is an adverse reaction, the nature or severity of which is not consistent with the applicable product information (e. g. , Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product)

Serious Adverse Events (SAEs) A serious adverse event is any untoward medical occurrence that at any dose: • • • results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, OR is a congenital anomaly/birth defect

Serious Adverse Events (SAEs) A serious adverse event is any untoward medical occurrence that at any dose: • • results in death, or is life-threatening, or requires inpatient hospitalization or prolongation of existing hospitalization, or results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect An AE is classified as serious if it poses a threat to the participant's life or function

Assessing an Adverse Event • Clear procedures and a specific list of AEs should be present in the study protocol • AEs should be evaluated for severity and relatedness to the treatment • Must be followed up at each visit until resolved • AEs should be followed up regardless of whether the participant continues in the study • All contact attempts should be documented in the chart

Adverse Event Reporting • All AEs and/or laboratory abnormalities should be reported to the sponsor within the time period defined in the protocol • Some AEs might lead to changes in the study or design of treatment if they are study related, especially SAEs • All SAEs should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e. g. , Investigator's Brochure) identifies as not needing immediate reporting The immediate reports should be followed promptly by detailed, written reports. • The immediate and follow-up reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects' names, personal identification numbers, and/or addresses. • Unexpected serious drug reactions must be reported according to regulatory and IRB requirements • The sponsor and IRB may need additional information about reported deaths (e. g. autopsy report) •

Adverse Event Reporting- IRB Report all adverse events promptly to Tufts University Dental Research Administration • • • DRA will help determine if the event requires immediate reporting to the IRB per regulatory requirements Immediate reporting is required in the following cases: Unexpected and/or inconsistent with risk information previously reviewed and approved by the IRB, AND • Related/possible related to research procedures • • Please see http: //viceprovost. tufts. edu/HSCIRB/policiesregulations/reportable-new-information/ for more details on what events require immediate reporting

CONFIDENTIALITY AND PRIVACY

Maintaining Confidentiality of Records A patient’s participation in a research study, and all of their study records MUST be kept confidential • • A breach of confidentiality occurs if any of this information is shared with a third party without either a court order or signed consent by the participant • When not in use, all written records must be kept in a secure room, in a locked cabinet, a safe, or other secure location. Each site must adopt written procedures to control access and use of all confidential documentation. • The primary (family) physician of a subject should only be informed of their participation in the trial after obtaining permission from the subject • Exceptions to confidentiality requirements: • • Criminal activity Suspected child abuse or neglect Request from armed forces or VA Medical emergencies • • • Research, audit, and evaluation activities Danger to self or others Communicable disease Court order Requirements of state law

Protected Health Information (PHI) Protected Health Information is information created or received by a covered entity that relates to past, present or future: • • • physical or mental condition, OR provision of healthcare, OR payment of healthcare PHI is any health information that identifies an individual OR with respect to which there is a reasonable basis to believe the information can be used to identify the individual

HIPAA • Health Insurance Portability and Accountability Act (HIPAA) of 1996 provides data privacy and security provisions for safeguarding medical information • The Department of Health and Human Services (DHHS) issued the HIPAA Privacy Rule to set national standards for the protection of certain health information in April 14, 2003 • The privacy rule applies to covered entities: A health plan • A health care clearinghouse • A health care organization that transmits any health care information electronically • • HIPAA regulations allow researchers to access and use PHI when necessary to conduct research

HIPAA Identifiers The HIPAA privacy rule sets forth policies to protect all individually identifiable health information that is held or transmitted by a covered entity. These are the 18 HIPAA Identifiers that are considered personally identifiable information: • Names • Certificate/license numbers • Street address & zip codes • • All elements of date (except year), including date of birth, admission or discharge date, and • date of death. (For participants over age 89, • even the year of birth cannot be disclosed) Vehicle identifiers and serial numbers, including license plate numbers Device identifiers and serial numbers URLs • Telephone numbers • Internet protocol address • Fax numbers • • E-mail addresses Biometric identifiers, including fingerprints and voiceprints Full-face photographic images • Social security numbers • • Medical record numbers • • Health plan beneficiary numbers Any other unique identifying number, characteristic, or code unless otherwise permitted by the Privacy Rule for reidentification (such as Axi. Um number) • Account numbers Data is only de-identified if it excludes all 18 HIPAA identifiers

TRIAL RECORDS AND REPORTS

Source Documents Source documents are original documents, data, and records created during a study, including: • • • Reports of diagnostic test results and laboratory notes Signed and dated informed consent documents Hospital records Participant diaries, surveys, checklists X-rays, photographs Recorded data from automated instruments Pharmacy dispensing records Case Report Forms (CRFs) on which data are recorded for the first time rather than extracted from other source documents Source data are all information in original records, and certified copies of original records, of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial • • Source data are contained in source documents

Progress Notes Progress notes are used to document a participant’s involvement in a study and all study-related care they receive. • Progress notes are source documents that are not entered into the study database • Progress notes are used at the site to monitor the progress of the study and to substantiate the data recorded in the case report forms • Progress notes should be thorough, and clear, yet concise. • • They should provide enough information about each participant’s path through the study so that all study related activities can be easily understood. • Clinical progress notes record information related to the treatment received by the participant during each visit • Research progress notes record information related to the participant’s involvement in the research phases of the study. • Research phases include determination of eligibility, follow-up visits, and data collected at treatment visits that are collected by staff not administering the treatment

Correcting an Error • Corrections to source documents should be made the day they were completed • To make a correction, cross out the error with a single line, make the correction, then initial and date to show who made the correction • When necessary, write an explanation of the correction (provides an audit trail) • White-out should never be used to correct an error • Changes to patient information should be noted in the patient chart Whenever possible, the participant should make their own corrections • A study personnel member should not make a correction on behalf of a participant (such as on an ICF or medical history form) •

Essential Documents Essential documents are those which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced • Essential documents serve to demonstrate the compliance of the PI, sponsor, and monitor with GCP standards, and all applicable regulatory requirements • • • These include: agreement between sponsor and PI/institution documenting financial aspects, IRB approval paperwork, investigator CVs, instructions for handling the IP, signed ICFs, completed CRFs, subject screening and enrollment logs Please section 8 of ICH E 6 GCP for a comprehensive list of all essential documents and their purposes These documents should be kept in the trial master files • • Either the study sponsor, or Dental Research Administration, will provide a regulatory binder for the study Direct access to all trial-related documents must be provided to the following entities to allow for auditing/inspection: • • • Study Sponsor Tufts University Dental Research Administration Quality-assurance monitors Auditors Other regulatory authorities

Study Monitoring • Studies are monitored to ensure that: The rights and well-being of human participants are protected • Reported study data are accurate, complete, and verifiable from source documents • The study is conducted in compliance with the currently approved protocol (including any amendments) as well as with GCP and all other applicable regulatory requirements • • The intent of monitoring is not to penalize individuals for mistakes, but to ensure that procedures and systems are in place to encourage high standards of data collection and management. • However, persistent noncompliance with quality standards can result in negative consequences for individuals, sites, or the study.

Record Retention • Essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region OR: • At least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product • Essential documents may need to be retained longer, if required by applicable regulatory requirement, or by agreement with the sponsor • It is the responsibility of the sponsor to inform the PI/institution as to when these documents no longer need to be retained • A study site has the responsibility of storing patient study records and maintaining confidentiality for the duration of the research study • For the purposes of this study network, Tufts University Dental Research Administration will collect study records from each site at the conclusion of the study and will store those records according to federal regulations

Progress Reporting • Per federal regulations, an IRB must conduct continuing review of previously approved research at intervals appropriate to the degree of risk, but not less than once per year • Key issues focused on at continuing review are: Risk assessment and monitoring; • Adequacy of the process for obtaining informed consent; • Local issues/Investigator and institutional issues; and • Research progress • • Continuing review is to be conducted before expiration of IRB approval • If approval lapses, research must stop until the IRB re-approves the research, or permission is approved by the IRB to continue • The PI must promptly provide written reports on any changes significantly affecting the conduct of the trial, and/or increasing risk to the subjects Within 5 business days to the IRB • Sponsor requirement will be outlined in the clinical trial agreement • • Any Data and Safety Monitoring Board report, and audit or inspection reports or findings issued by regulatory agencies, cooperative research groups, contract research organizations, the sponsor or the funding agency must be provided to the IRB

Final Reports • Upon completion of the trial, the PI must provide the sponsor will all required reports • Where applicable, the PI should provide a final report with a summary of the trial’s outcomes to the IRB and the regulatory authority(ies) • TUSDM DRA should be informed when research activity is complete to assist with closing out the study with the IRB