Quality Assurance/Quality Improvement
Key Research Regulations and Institutional Policies
Purpose: This table enables research personnel to reference key regulations and institutional policies.
Focused topic area
Protocol
[1] Current version
[2,3,4] Previous version,
Amendments, Protocol and
amendment signature pages
Investigator Brochure (IB)
[1] Current version
[2] Previous version
QA Support/Policy/Regulations
[1] 21 CFR 312.60 and 21 CFR 812.100 An investigator is responsible for ensuring that an investigation is conducted according to the
signed agreement, the investigational plan and applicable FDA regulations, for protecting the rights, safety, and welfare of subjects under
the investigator's care, and for the control of drug/devices under investigation;
21 CFR 312.23 (a) (6) A sponsor is required to submit detailed protocols describing all aspects of the study.
[2,3,4] 21 CFR 312.30 (a) (2)(d) (3) (e) A sponsor is required to submit protocol amendment for a new protocol or a change in protocol
before its implementation;
ICH GCP 4.5 The investigator/institution and the sponsor are required to sign the protocol, or an alternative contract, to confirm their
agreement;
ICH GCP 8.3.2 The investigator is required to document revisions of trial- related documents that take effect during trial.
[1] 21 CFR 312.55 (a) The sponsor is required to give each participating clinical investigator an investigator brochure;
ICH GCP 7.0 The sponsor is responsible for ensuring that an up-to-date IB is made available to the investigator(s) and the investigators
are responsible for providing the up-to-date IB to the responsible IRBs/IECs;
ICH GCP 8.2.1 The investigator is required to document that relevant and current scientific information about the investigational product
has been provided to the investigator.
[2] 21 CFR 312.55 (b) The sponsor is required to inform of new observations, distributed to investigators by means of periodically
revised investigator brochures;
ICH GCP 7.2.1 The sponsor is required to submit edition number of the IB, and a reference to the number and date of the edition it
supersedes;
ICH GCP 8.3.1 The investigator is required to document that investigator is informed in a timely manner of relevant information as it
becomes available.
Focused topic area
FDA 1571
[1] Current signed and dated
[2] Previous signed and dated
FDA 1572
[1] Current signed and dated
[2] Previous signed and dated
Financial Disclosure Certification
(FDC), Conflict of Interest (COI)
Current version, Previous version
Informed Consent Form
[1,2] Current version, Previous
version
[3] ICF obtained prior to participation
[4] ICF documentation
[5] Sufficient opportunity
[6] ICF revision and re-consenting
[7] Obtaining permission from LAR
QA Support/Policy/Regulations
[1] 21 CFR 312.23 (a) A sponsor who intends to conduct investigational new drug (IND) clinical investigations is required to submit a
Cover sheet (Form FDA-1571).
[2] 21 CFR 312.31(a) A sponsor is required to report any amendment to essential information on the IND that is not within the scope of a
protocol amendment, IND safety reports, or annual report.
[1] 21 CFR 312.53 (c) (1) Before permitting an investigator to begin participation in an IND investigation, the sponsor is required to
obtain a signed investigator statement (Form FDA-1572).
[2] FDA Information sheet guidance for sponsors, clinical investigators and IRBs: Frequently asked questions- Statement of Investigator
(Form FDA 1572) (7) An investigator is required to complete and sign a new 1572 when a new investigator is added to the study.
21 CFR 54.4 (b) The clinical investigator is required to provide to the sponsor of the covered study sufficient accurate financial
information to allow the sponsor to submit complete and accurate certification or disclosure statements as required. The investigator shall
promptly update this information if any relevant changes occur in the course of the investigation or for 1 year following completion of the
study;
ICH GCP 8.2.4 The investigator is required to document the financial agreement between the investigator/ institution and the sponsor for
the trial;
Drexel University Investigator Manual, Version 3/6/2014, 04/34, All individuals involved in the design, conduct, or reporting of research
are required to disclose the financial interests;
Drexel University Investigator Manual, Version 3/6/2014, 08/34, All investigators are required to submit an updated disclosure of
financial interests within thirty days of discovering or acquiring a new financial interest.
[1,2] 21 CFR 312.60 An investigator is required to obtain the informed consent of each human subject to whom the drug is administered;
ICH GCP 8.3.2 The investigator is required to document revisions of informed consent form that take effect during trial;
Drexel University Investigator Manual, Version 3/6/2014, 08/34, The investigator must ensure that consent or permission is obtained in
accordance with the relevant current protocol as approved by the IRB.
[3] 21 CFR 312.62 (b) The case history for each individual is required to document that informed consent was obtained prior to
participation in the study.
[4] 45 CFR 46.117 and 21 CFR 50.27 (a) The investigator is required to document informed consent by the use of a written consent form
approved by the IRB and signed by the subject or the subject's legally authorized representative, a copy is required to be given to the
person signing the form;
812.140 (a) (3) (i) The investigator is required to provide documents evidencing informed consent and, for any use of a device by the
investigator without informed consent, any written concurrence of a licensed physician and a brief description of the circumstances
justifying the failure to obtain informed consent;
ICH GCP 8.2.3 The investigator is required to document that subjects will be given appropriate written information to support their
ability to give fully informed consent.
[5] 45 CFR 46.116 and 21CRF 50.20 An investigator is required to consent only under circumstances that provide the prospective subject
or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue
influence.
[6] ICH GCP 4.8.2 The investigator is required to revise the consent form whenever important new information becomes available that
may be relevant to the subject’s consent, any revised written informed consent form, and written information should receive the
IRB/IEC's approval/favorable opinion in advance of use;
ICH GCP 4.8.2 The investigator is required to inform the subject or the subject’s legally acceptable representative in a timely manner any
new information relevant to participation and communication of this information should be documented.
[7] Drexel University Investigator Manual, Version 3/6/2014, 09/34, The investigator is required to ascertain from the LAR whether there
are any individuals in a higher level of priority and, if so, obtain the consent of the individual in the higher level;
Drexel University Investigator Manual HRP 103 notes, If the subject regains the capacity to provide consent, an investigator is required to
obtain the consent of the subject for continued participation in the research
[8] Short form
IRB Approvals
[1] Initial submission
[8] 21 CFR 50.27 (b) (2) A short form written consent document stating that the elements of informed consent have been presented orally
to the subject or the subject's legally authorized representative. When this method is used, a witness to the oral presentation is required.
Also, the IRB shall approve a written summary of what is to be said to the subject or the representative. Only the short form itself is to be
signed by the subject or the representative. However, the witness shall sign both the short form and a copy of the summary, and the
person actually obtaining the consent shall sign a copy of the summary. A copy of the summary shall be given to the subject or the
representative in addition to a copy of the short form.
[1] 21 CFR 312.66 An investigator is required to assure that an IRB will be responsible for the initial and continuing review and approval
of the proposed clinical study;
21 CFR 56.109 (a) An IRB shall review and have authority to approve, require modifications in (to secure approval), or disapprove all
research activities covered by these regulations;
21 CFR 812.62 An IRB shall review and have authority to approve, require modifications in (to secure approval), or disapprove all
investigations covered by IDE;
ICH GCP 8.2.7 The investigator is required to document that the trial has been subject to IRB/IEC review and given approval/favorable
opinion, identify the version number and date of the document(s);
Drexel University Investigator Manual, Version 3/6/2014, 11/34, If approval of human research expires, all human research procedures
related to the protocol under review must cease.
[2] Continuing review
[3] Amendments
[2,3] 21 CRF 312.23 (a) (1) (iv) A sponsor is required to have commitment that an IRB will be responsible for the initial and continuing
review and approval of each of the studies in the proposed clinical investigation and that the investigator will report to the IRB proposed
changes in the research activity;
21 CFR 56.109 (f) and 45 CFR 46.109 (e) An IRB is required to conduct continuing review of research covered by these regulations at
intervals appropriate to the degree of risk, but not less than once per year, and shall have authority to observe or have a third party
observe the consent process and the research;
21 CFR 812.64 The IRB shall conduct its continuing review of an investigation in accordance with IDE;
ICH GCP 3.1.4 The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to
human subjects, but at least once per year;
ICH GCP 8.3.2 An investigator is required to document revisions of these trial- related documents that take effect during trial;
Drexel University Investigator Manual, Version 3/6/2014, 05/34, The investigator is required to maintain electronic copies of all
information submitted to the IRB in case revisions are required;
[4] Advertisement/ Recruitment
material
[5] Patient materials (education,
reminder cards, etc.)
[4,5] 21 CFR 56.109 (b) and 45 CFR 46.109 (b) The investigator is required to provide the subjects with information when in the IRB's
judgment the information would meaningfully add to the protection of the rights and welfare of subjects;
ICH GCP 3.1.2 The IRB/IEC is required to obtain trial subject recruitment procedures (e.g., advertisements), written information to be
provided to subjects, Investigator's Brochure (IB), available safety information, information about payments and compensation available
to subjects, and any other documents that the IRB/IEC may require to fulfill its responsibilities.
[6] Response to Serious Adverse
Events (SAE)s
[7] Response to IND reports
[6,7] 21 CFR 56.109 (e) and 45 CFR 46.109 (d) An IRB is required to notify investigators and the institution in writing of its decision to
approve or disapprove the proposed research activity, or of modifications required to secure IRB approval of the research activity;
ICH GCP 4.11.1 The investigator is required to comply with the applicable regulatory requirement(s) related to the reporting of
unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB/IEC;
ICH GCP 5.11.3 The sponsor is required to obtain from the investigator/institution documentation and dates of any IRB/IEC reapprovals/reevaluations with favorable opinion, and of any withdrawals or suspensions of approval/favorable opinion;
ICH GCP 8.3.3 The investigator is required to document that the amendment(s) and/or revision(s) have been subject to IRB/IEC review
and were given approval/favorable opinion, identify the version number and date of the document(s).
[8] Prior approvals
IRB Roster
Current, Previous
Laboratory
[1] Current normal ranges
[2] Previous normal ranges
[8] ICH GCP 5.10 Before initiating the clinical trial(s), the investigator is required to submit any application(s) to the appropriate
authority(ies) for review, acceptance, and/or permission to begin the trial(s);
ICH GCP 3.3.6 The investigator is required to ensure that no subject is be admitted to a trial or participate in any trial related activities
before the IRB issues its written approval/favorable opinion of the trial;
21 CFR 56.103 (a) A clinical investigation will not be initiated unless the investigation has been reviewed and approved by, and remain
subject to continuing review by, an Institutional review board (IRB);
45 CFR 46.103(b)(4) Changes in approved research, during the period for which IRB approval has already been given, may not be
initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the subject;
Drexel University Investigator Manual, Version 3/6/2014, 08/34, Do not start human research activities until the investigator have the
final IRB approval letter;
Drexel University Investigator Manual, Version 3/6/2014, 10/34, The research must continue to be conducted without inclusion of the
modification until IRB approval is received.
45 CFR 46.103 (b) (3) The IRB is required to provide a list of IRB members identified by name; earned degrees; representative capacity;
indications of experience such as board certifications, licenses, etc., sufficient to describe each member's chief anticipated contributions to
IRB deliberations; and any employment or other relationship between each member and the institution; for example: full-time employee,
part-time employee, member of governing panel or board, stockholder, paid or unpaid consultant;
ICH GCP 3.2.1 The investigator is required to maintain a list of IRB/IEC members and their qualifications.
[1,2] DAIDS Guideline for GCLP (1) The study plan is required to include reference ranges, referral laboratory information, and
transmission of results;
21 CFR 58.81 (c) Each laboratory area is required to have immediately available laboratory manuals and standard operating procedures
relative to the laboratory procedures being performed;
ICH GCP 8.2.11The investigator is required to document normal values and/or ranges of the tests;
ICH GCP 8.3.6 The investigator is required to document normal values and ranges that are revised during the trial.
[3] Lab certification (CAP & CLIA)
[4] Previous lab certification
[3,4] 42 CFR 493.45 Registration certificate is required for all laboratories performing test procedures of moderate complexity or high
complexity, or both;
ICH GCP 8.2.12 The investigator is required to document competence of facility to perform required test(s), and support reliability of
results;
ICH GCP 8.3.7 The investigator is required to document that tests remain adequate throughout the trial period.
[5] Lab director’s CV (current and
previous)
[6] Lab director’s license (current and
previous)
[5,6] 42 CFR 493.1357 The laboratory director must be qualified to manage and direct the laboratory personnel. The laboratory director
must possess a current license as a laboratory director issued by the State in which the laboratory is located.
Focused topic area
Specimen storage
[1] Securely stored
[2] Labeled per protocol
QA Support/Policy/Regulations
[1,2] OHRP Policy Guidance, Repositories, Tissue Storage: Issues to Consider in the Research Use of Stored Data or Tissues, (November
7, 1997) Operation of the repository and its data management center is subject to oversight by an IRB. The IRB is required to review and
approve a protocol specifying the conditions under which data and specimens may be accepted and shared, and ensuring adequate
provisions to protect the privacy of subjects and maintain the confidentiality of data. The IRB is required to review and approve a sample
collection protocol and informed consent document for distribution to tissue collectors and their local IRBs. A Certificate of
Confidentiality should be obtained to protect confidentiality of repository specimens and data;
ICH GCP 8.3.25 The investigator is required to document location and identification of retained samples if assays need to be repeated.
Randomization and Un-blinding
[1] Randomization and unblinding procedures
[1] DMID Pharmacy guidelines and Instructions (January 2007) 7.1 The process by which a subject is assigned a subject identification
number varies according to the site and the protocol; The treatment assignment information must be maintained in a secure location and
available only to un-blinded study personnel, such as the research pharmacist;
DMID Pharmacy guidelines and Instructions (January 2007) 7.2 The pharmacist, investigator, DMID, and/or sponsor must agree on a
procedure for un-blinding the treatment assignment in an emergency;
ICH GCP 4.7 The investigator should follow the trial's randomization procedures, if any, and should ensure that the code is broken only
in accordance with the protocol. If the trial is blinded, the investigator should promptly document and explain to the sponsor any
premature un-blinding (e.g., accidental un-blinding, un-blinding due to a serious adverse event) of the investigational product(s);
[2] Randomization and decoding list
[2] ICH GCP 8.2.17 The investigator is required to maintain master randomization list to document, how, in case of an emergency,
identity of blinded investigational product can be revealed without breaking the blind for the remaining subjects’ treatment;
ICH GCP 8.2.18 The investigator is required to maintain master randomization list to document method for randomization of trial
population;
ICH GCP 8.4.6 The investigator is required to return treatment allocation and decoding documents to the sponsor to document any
decoding that may have occurred.
Screening and Enrolment of
subjects/ logs
ICH GCP 8.3.20 The investigator is required to maintain subject screening log to document identification of subjects who entered
pretrial screening;
FDA Information Sheet Guidance: (Screening tests prior to enrollment) Informed consent must be obtained prior to initiation of any
clinical screening procedures that is performed solely for the purpose of determining eligibility for research;
ICH GCP 8.3.22 The investigator is required to maintain subject enrollment log to document chronological enrollment of subjects by trial
number;
ICH GCP 8.3.21 The investigator is required to maintain subject identification code list to document that investigator/ institution keeps a
confidential list of names of all subjects allocated to trial numbers on enrolling in the trial;
ICH GCP 8.4.3 The investigator is required to maintain completed subject identification code list to permit identification of all subjects
enrolled in the trial in case follow-up is required. List should be kept in a confidential manner and for agreed upon time.
Focused topic area
QA Support/Policy/Regulations
Study Monitoring
[1] Monitoring activities
[1] 21 CFR 312.23 (a) (6) (iii) (g) A clinical trial protocol is required to include a description of clinical procedures, laboratory tests, or
other measures to be taken to monitor the effects of the drug in human subjects and to minimize risk;
21 CFR 56.111 (a) (6) The research plan is required to make adequate provision for monitoring the data collected to ensure the safety of
subjects;
ICH GCP 5.18 The sponsor is required to conduct monitoring based on the objective, purpose, design, complexity, blinding, size, and
endpoints of the trial in the form of on-site monitoring, before, during, and after the trial;
ICH GCP 5.19 Audit as part of implementing quality assurance is required to be independent of and separate from routine monitoring or
quality control functions, to evaluate trial conduct
and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements;
FDA Guideline for Monitoring of Clinical Investigations (IV) The sponsor is required to perform risk based monitoring by prospectively
identifying critical data and processes, then perform a risk assessment to identify and understand the risks that could affect the collection
of critical data or the performance of critical processes, and then develop a monitoring plan that focuses on the important and likely risks
to critical data and processes.
[2] Monitoring reports and logs
(Initiation to Close-out visit)
[2] ICH GCP 8.2.19 Pretrial monitoring report is required to document that the site is suitable for the trial;
ICH GCP 8.2.20 Trial initiation monitoring report is required to document that the trial procedures were reviewed with the investigator
and investigator’s trial staff;
ICH GCP 8.3.10 Monitoring visit reports are required to document site visits by, and findings of, the monitor;
ICH GCP 8.4.4 Audit certificate is required to document that audit was performed (if required by protocol);
ICH GCP 8.4.5 Final trial close-out monitoring report is required to document that all activities required for trial close-out are completed,
and copies of essential documents are held in the appropriate files.
Investigator qualifications,
responsibilities and training
[1] CV, experience, education,
expertise, training (license)
[1] 21 CFR 312.23 (a) (6) (iii) (b) The sponsor is required to obtain the name and address and a statement of the qualifications
(curriculum vitae or other statement of qualifications) of each investigator, and the name of each sub-investigator (e.g., research fellow,
resident) working under the supervision of the investigator;
21 CFR 312.53 (a) A sponsor is required to select only investigators qualified by training and experience as appropriate experts to
investigate the drug;
21 CFR 312.53 (c)(2) Before permitting an investigator to begin participation in an investigation, the sponsor is required to obtain a
curriculum vitae or other statement of qualifications of the investigator showing the education, training, and experience that qualifies the
investigator as an expert in the clinical investigation of the drug for the use under investigation;
21 CFR 812.43 (c)(1) A sponsor is required to obtain from investigator a signed agreement that includes curriculum vitae;
ICH GCP 4.1.1 The investigator(s) must be qualified by education, training, and experience to assume responsibility for the proper
conduct of the trial, should meet all the qualifications specified by the applicable regulatory requirement(s), and should provide evidence
of such qualifications through up-to-date curriculum vitae and/or other relevant documentation requested by the sponsor, the IRB/IEC,
and/or the regulatory authority(ies);
ICH GCP 8.2.10 The investigator is required to document qualifications and eligibility to conduct trial and/or provide medical
supervision of subjects;
ICH GCP 8.3.5 The investigator is required to document qualifications and eligibility to conduct trial and/or provide medical supervision
of subjects for new investigators;
Drexel University Investigator Manual, Version 3/6/2014, 04/34, Investigators and staff conducting human subject research must
complete the Learner Group specific Collaborative Institutional Training Initiative (CITI) human subject online training.
[2] Sufficient time, resources
[2] ICH GCP 4.2.1 The investigator must be able to demonstrate (e.g., based on retrospective data) a potential for recruiting the required
number of suitable subjects within the agreed recruitment period;
ICH GCP 4.2.2 The investigator is required to have sufficient time to properly conduct and complete the trial within the agreed trial
period;
ICH GCP 4.2.3 The investigator is required to have available an adequate number of qualified staff and adequate facilities for the
foreseen duration of the trial to conduct the trial properly and safely;
ICH GCP 5.6.1 The sponsor is responsible for selecting investigator(s)/institution(s) qualified by training and experience and should have
adequate resources to properly conduct the trial for which the investigator is selected;
[3] Delegation of responsibility/
Signature log, Training log
[3] 21 CFR 312.53 (c)(1)(vi)(c) The investigator is required to personally conduct or supervise the described investigation(s);
21 CFR 312.53 (c)(1)(vi)(g) The investigator is required to ensure that all associates, colleagues, and employees assisting in the conduct
of the study(ies) are informed about their obligations in meeting the study commitments;
FDA Guidance for Industry: Investigator Responsibilities , Protecting the Rights, Safety and Welfare of Study Subjects, October, 2009
(III) (A) (1) When tasks are delegated by an investigator, the investigator is responsible for providing adequate training and supervision
of those to whom tasks are delegated;
ICH GCP 4.2.4 The investigator is required to ensure that all persons assisting with the trial are adequately informed about the protocol,
the investigational product(s), and their trial-related duties and functions;
ICH GCP 4.3.1 A qualified physician (or dentist, when appropriate), who is an investigator or a sub-investigator for the trial, is required
to be responsible for all trial-related medical (or dental) decisions;
ICH GCP 4.3.3 The investigator is required to inform the subject's primary physician about the subject's participation in the trial if the
subject has a primary physician and if the subject agrees to the primary physician being informed;
ICH GCP 4.5.1 The investigator/institution is required to conduct the trial in compliance with the protocol agreed to by the sponsor and
regulatory authority(ies), and which was given approval/favorable opinion by the IRB/IEC. The investigator /institution and the sponsor
should sign the protocol, or an alternative contract, to confirm their agreement;
ICH GCP 5.7 Prior to initiating a trial, the sponsor is required to define, establish, and allocate all trial-related
duties and functions;
ICH GCP 8.3.24. The investigator is required to document signatures and initials of all persons authorized, responsibilities and dates
responsibilities began and ended.
Case Report Forms (CRF)s
[1] Copy of most recently approved
sample CRF
[2] CRF Transmittal Log
[1] 21 CFR 312.62 (b) An investigator is required to prepare and maintain adequate and accurate case histories that record all
observations and other data pertinent to the investigation;
ICH GCP 8.2.2 An investigator is required to keep sample CRF to document investigator and sponsor agreement to the
protocol/amendment(s) and CRF;
ICH GCP 8.2.7 An investigator is required to keep dated/ documented approval of CRF to document that the trial has been subject to
IRB/IEC review and given approval/favorable opinion, identify the version number and date of the document(s).
[2] ICH GCP 4.9.1 The investigator is required to ensure the accuracy, completeness, legibility, and timeliness of the data reported to the
sponsor in the CRFs and in all required reports;
ICH GCP 4.9.3 The investigator is required to ensure any change or correction to a CRF to be dated, initialed, and explained (if
necessary) and should not obscure the original entry (i.e., an audit trail should be maintained); this applies to both written and electronic
changes or corrections. Sponsors should provide guidance to investigators and/or the investigators' designated representatives on making
such corrections;
FDA Guidance for Industry: Investigator Responsibilities, Protecting the Rights, Safety and Welfare of Study Subjects, October, 2009
(III) (A) (3) The investigator should develop procedures for ensuring source data are accurate, contemporaneous, and original,
information in source documents is accurately captured on the (CRF)s, dealing with data queries and discrepancies identified by the study
monitor;
ICG GCP 8.3.14 The investigator is required to include signed, dated and completed case report forms (CRF)s to document that the
investigator or authorized member of the investigator’s staff confirms the observations recorded;
ICH GCP 8.3.15 The investigator is required to document all changes/additions or corrections made to CRF after initial data were
recorded;
ICH GCP 8.3.24 The investigator is required to include signature sheet to document signatures and initials of all persons authorized to
make entries and/or corrections on CRFs.
[3] Source documents
Adverse Events (AE)s and Serious
Adverse Events (SAE)s,
[1] SAE reporting form and
instructions
[3] ICH GCP 8.3.13 An investigator is required to obtain source documents to document the existence of the subject and substantiate
integrity of trial data collected and to include original documents related to the trial, to medical treatment and history of the subject.
[1] 21 CFR 312.32 (c)(1)(v) The sponsor must submit each IND safety report in a narrative format or on FDA Form 3500A or in an
electronic format that FDA can process, FDA will periodically issue guidance on how to provide the electronic submission;
21 CFR 312.64 (b) An investigator must immediately report to the sponsor any serious adverse event, whether or not considered drug
related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable
possibility that the drug caused the event;
21CFR 812.150 (a) (1) An investigator shall submit to the sponsor and to the reviewing IRB a report of any unanticipated adverse device
effect occurring during an investigation as soon as possible, but in no event later than 10 working days after the investigator first learns of
the effect;
ICH GCP 4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be
reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol.
[2] IND safety letters
[2] 21 CFR 312.32 (c)(1) The sponsor must notify FDA and all participating investigators in an IND safety report of potential serious
risks, from clinical trials or any other source, as soon as possible. In each IND safety report, the sponsor must identify all IND safety
reports previously submitted to FDA concerning a similar suspected adverse reaction, and must analyze the significance of the suspected
adverse reaction in light of previous, similar reports or any other relevant information.
[3] Completed SAE reports (or notes
of their location) and logs
[3] 21 CFR 812.140 (a) (3) (ii) All relevant observations, including records concerning adverse device effects (whether anticipated or
unanticipated), information and data on the condition of each subject upon entering, and during the course of, the investigation, including
information about relevant previous medical history and the results of all diagnostic tests;
ICH GCP 5.17.3 The sponsor should submit to the regulatory authority(ies) all safety updates and periodic reports, as required by
applicable regulatory requirements;
ICH GCP 8.3.16 The investigator is required to document notification by originating investigator to sponsor of serious adverse events and
related reports;
ICH GCP 8.3.17 The investigator is required to document notification by sponsor and/or investigator, where applicable, to regulatory
authorities and IRB(s)/IEC(s) of unexpected serious adverse drug reactions and of other safety information;
ICH GCP 8.3.18 The investigator is required to document notification by sponsor to investigators of safety information;
NIH Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multicenter Trials, June 11, (1999) An
investigator is responsible for the accurate documentation, investigation and follow-up of all possible study-related adverse events.
Focused topic area
QA Support/Policy/Regulations
Protocol deviation
21 CFR 312.66 The investigator required to assure that he or she will promptly report to the IRB all changes in the research activity and
all unanticipated problems involving risk to human subjects or others, and that he or she will not make any changes in the research
without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects;
21 CFR 812.140 (a) (4) The investigator is required to maintain accurate, complete, and current records relating to the investigator's
participation in an investigation with documents showing the dates of and reasons for each deviation from the protocol;
21 CFR 812.150 (a) (4) An investigator is required to notify the sponsor and the reviewing IRB of any deviation from the investigational
plan to protect the life or physical well-being of a subject in an emergency. Such notice shall be given as soon as possible, but in no event
later than 5 working days after the emergency occurred. Except in such an emergency, prior approval by the sponsor is required for
changes in or deviations from a plan, and if these changes or deviations may affect the scientific soundness of the plan or the rights,
safety, or welfare of human subjects, FDA and IRB also is required;
DMID Pharmacy guidelines and Instructions (January 2007) (8.2) Study drug related protocol deviations must be reported as specified in
protocol and addressed in the study-specific source documents;
ICH GCP 4.5.2 The investigator should not implement any deviation from, or changes of, the protocol without agreement by the sponsor
and prior review and documented approval/ favorable opinion from the IRB/IEC of an amendment;
ICH GCP 8.3.11 The investigator is required to document any agreements or significant discussions regarding trial administration,
protocol violations, trial conduct and adverse event (AE) reporting.
Investigational Product (IP)
[1] Sponsor’s responsibility to provide
and maintain IP handling and storage
information
[2] Sponsor’s responsibility to
maintain IP shipping and return
information
[1] 21 CFR 312.23 (a) (7) The sponsor is required to provide information on the composition, manufacture, and control of the drug
substance and the drug product;
21 CFR 812.36 (c)(vi) The sponsor is required to provide instructions for treatment use of an investigational device and all other labeling
as required by FDA;
ICH GCP 5.13.2 The sponsor is required to determine, for the investigational product(s), acceptable storage temperatures, storage
conditions (e.g., protection from light), storage times, reconstitution fluids and procedures, and devices for product infusion, if any. The
sponsor is required to inform all involved parties (e.g., monitors, investigators, pharmacists, storage managers) of these determinations;
ICH GCP 5.14.3 The sponsor is required to ensure that written procedures include instructions that the investigator/institution should
follow for the handling and storage of investigational product(s) for the trial and documentation thereof. The procedures to address
adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from subjects, and return of unused investigational
product(s) to the sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory
requirement(s).
[2] 21 CFR312.57 (a) A sponsor is required to maintain adequate records showing the receipt, shipment, or other disposition of the
investigational drug. These records are required to include, as appropriate, the name of the investigator to whom the drug is shipped, and
the date, quantity, and batch or code mark of each such shipment;
21 CFR 312.59 The sponsor is required to assure the return of all unused supplies of the investigational drug from each individual
investigator whose participation in the investigation is discontinued or terminated. The sponsor may authorize alternative disposition of
unused supplies of the investigational drug provided this alternative disposition does not expose humans to risks from the drug. The
sponsor is required to maintain written records of any disposition of the drug;
21 CFR 812.46 (a) A sponsor who discovers that an investigator is not complying with the signed agreement, the investigational plan, the
requirements of applicable FDA regulations, or any conditions of approval imposed by the reviewing IRB or FDA shall promptly either
secure compliance, or discontinue shipments of the device to the investigator and terminate the investigator's participation in the
investigation. A sponsor will also require such an investigator to dispose of or return the device.
[3] Administration of IP by
investigator
[3] 21 CFR 312.61 An investigator is required to administer the drug only to subjects under the investigator's personal supervision or
under the supervision of a sub-investigator responsible to the investigator. The investigator shall not supply the investigational drug to
any person not authorized to receive it;
21 CFR 312.62 An investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use
by subjects. If the investigation is terminated, suspended, discontinued, or completed, the investigator shall return the unused supplies of
the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the drug;
21 CFR 812.110 (c) An investigator will permit an investigational device to be used only with subjects under the investigator's
supervision. An investigator will not supply an investigational device to any person not authorized under this part to receive it;
21 CRF 812.110 (e) Upon completion or termination of a clinical investigation or the investigator's part of an investigation, or at the
sponsor's request, an investigator is required to return to the sponsor any remaining supply of the device or otherwise dispose of the
device as the sponsor directs;
21 CFR 312.69 The investigator is required to take adequate precautions, including storage of the investigational drug in a securely
locked, substantially constructed cabinet, or other securely locked, substantially constructed enclosure, access to which is limited, to
prevent theft or diversion of the substance into illegal channels of distribution;
ICH GCP 4.6.5 The investigator should ensure that the investigational product(s) are used only in accordance with the approved protocol;
Drexel University Investigator Manual, Version 3/6/2014, 12/34, For emergency use of an unapproved drug or biologic in a lifethreatening situation without prior IRB review, the investigator will need to submit a report of the use to the IRB within five days of the
use and submit an IRB application for initial review within 30 days.
[4] Investigator’s responsibility to
maintain adequate IP records
[4] 21 CFR 312.62 (a) An investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity,
and use by subjects. If the investigation is terminated, suspended, discontinued, or completed, the investigator shall return the unused
supplies of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the drug;
21 CFR 812.140 (a) (2) An investigator is required to maintain records of receipt, use or disposition of a device that relate to the type and
quantity of the device, the dates of its receipt, and the batch number or code mark, the names of all persons who received, used, or
disposed of each device, why and how many units of the device have been returned to the sponsor, repaired, or otherwise disposed of;
ICH GCP 4.6.3 The investigator/institution and/or a pharmacist or other appropriate individual, who is designated by the
investigator/institution, is required to maintain records of the product's delivery to the trial site, the inventory at the site, the use by each
subject, and the return to the sponsor or alternative disposition of unused product(s). These records should include dates, quantities,
batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and trial
subjects. Investigators are required to maintain records that document adequately that the subjects were provided the doses specified by
the protocol and reconcile all investigational product(s) received from the sponsor.
[5] IP/ Drug accountability log,
Shipping and maintenance logs,
receipt/packing records, supply form
[5] DMID Pharmacy guidelines and Instructions (January 2007) (5.2.5) All drugs dispensed in a research protocol is required to be
accounted for in an ongoing study product accountability log or dispensing log, may take the form of a continuous computerized record or
a paper document;
DMID Pharmacy guidelines and Instructions (January 2007) (5.2.6) Any time a study product is returned to the product supplier,
destroyed on site, or is transferred from one protocol to another, this occurrence must be documented in the accountability log(s);
ICH GCP 8.2.13 The investigator is required to document compliance with applicable labeling regulations and appropriateness of
instructions provided to the subjects;
ICH GCP 8.2.14 The investigator is required to document instructions needed to ensure proper storage, packaging, dispensing, and
disposition of investigational products and trial-related materials;
ICH GCP 8.2.15 The investigator is required to document shipment dates, batch numbers, and method of shipment of investigational
product(s) and trial- related materials, it allows tracking of product batch, review of shipping conditions, and accountability;
ICH GCP 8.4.1 The investigator is required to document that the investigational product(s) have been used according to the protocol and
to document the final accounting of investigational product(s) received at the site, dispensed to subjects, returned by the subjects, and
returned to sponsor;
[6] IVRS/ IXRS worksheet/ receipts
[7] Temperature log, Temperature
excursion record log
Correspondence
[1] Study contacts- list of important
study related contacts
ICH GCP 8.4.2 The investigator is required to document destruction of unused investigational product(s) by sponsor or at site.
[6] 21 CFR 11.10 The sponsor/investigator using closed systems to create, modify, maintain, or transmit electronic records is required to
employ procedures and controls designed to ensure the authenticity, integrity, and, when appropriate, the confidentiality of electronic
records, and to ensure that the signer cannot readily repudiate the signed record as not genuine;
21 CFR 11.10 (c) The sponsor/investigator is required to ensure protection of records to enable their accurate and ready retrieval
throughout the records retention period;
21 CFR 11.10 (e) The sponsor/investigator is required to ensure the use of secure, computer-generated, time-stamped audit trails to
independently record the date and time of operator entries and actions that create, modify, or delete electronic records. Record changes
shall not obscure previously recorded information. Such audit trail documentation is required to be retained for a period at least as long as
that required for the subject electronic records and shall be available for agency review and copying.
[7] DMID Pharmacy guidelines and Instructions (January 2007) (5.2.2) Temperature logs must be maintained for areas where study
products are stored. If, for any reason, temperature conditions have not been preserved, the occurrence must be documented as well;
ICH GCP 4.6.4 The investigational product(s) is required to be stored as specified by the sponsor and in accordance with applicable
regulatory requirement(s).
[1] 21 CFR 312.53 (c) (1) (viii) The investigator is required to maintain a list of the names of the sub-investigators (e.g., research
fellows, residents) who will be assisting the investigator in the conduct of the investigation(s);
ICH GCP 4.1.5 The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated
significant trial-related duties.
[2] IRB interim report letters
[2] ICH GCP 5.22 The sponsor is required to ensure that
the clinical trial/study reports are prepared and provided to the regulatory agency(ies) as required by the applicable regulatory
requirement(s);
ICH GCP 8.3.19 The investigator is required to document interim or annual reports provided to IRB/IEC and to authority(ies);
ICH GCP 8.4.7 The investigator is required to document final report to IRB/IEC and regulatory authority(ies).
[3] IRB notifications (Disapproval,
deferral, modification, etc.)
[4] Response to IRB actions
[3,4] 45 CFR 46.109 (a) An IRB is required to notify investigators and the institution in writing of its decision to approve or disapprove
the proposed research activity, or of modifications required to secure IRB approval of the research activity. If the IRB decides to
disapprove a research activity, it shall include in its written notification a statement of the reasons for its decision and give the
investigator an opportunity to respond in person or in writing;
45 CFR 46.115 (a) (2) An IRB is required to maintain copies of all research proposals reviewed, scientific evaluations, if any, that
accompany the proposals, approved sample consent documents, progress reports submitted by investigators, and reports of injuries to
subjects;
45 CFR 46.115 (a) (4) An IRB is required to maintain copies of all correspondence between the IRB and the investigators;
ICH GCP 8.3.3 The investigator is required to maintain copies of dated, documents approval/favorable opinion of IRB/IEC to document
that the amendment(s) and/or revision(s) have been subject to IRB/IEC review and were given approval/favorable opinion.
[5] Sponsor/CRO letters
[6] Sponsor/CRO meeting notes
[5,6] 21 CFR 312.55 (b) The sponsor is required to keep each participating investigator informed of new observations discovered by or
reported to the sponsor on the drug, particularly with respect to adverse effects and safe use;
ICH GCP 4.9.4 The investigator/institution is required to maintain the trial documents as required by the applicable regulatory
requirement(s). The investigator/institution should take measures to prevent accidental or premature destruction of these documents;
ICH GCP 4.10.2 The investigator is required to promptly provide written reports to the sponsor, the IRB/IEC and, where required by the
applicable regulatory requirements, the institution on any changes significantly affecting the conduct of
the trial, and/or increasing the risk to subjects;
ICH GCP 8.3.11The investigator is required to document any agreements or significant discussions regarding trial such as administration,
protocol violations, trial conduct and adverse event (AE) reporting;
ICH GCP 8.4.5 The investigator is required to document that all activities required for trial close-out are completed, and copies of
essential documents are held in the appropriate files.
[7] Research team letters
[8] Research team meeting notes
[9] Email and telephone
correspondence (IRB, Sponsor/CRO,
Research team, etc.)
[7,8, 9] 21 CFR 312.53 (c) (1) (vi) (g) The investigator is required to ensure all associates, colleagues, and employees assisting in the
conduct of the study(ies) are informed about their obligations in meeting the above commitments;
21 CFR 11.2 (a) For records required to be maintained, investigators may use electronic records in lieu of paper records or electronic
signatures in lieu of traditional signatures;
21 CFR 814.140 (a) (1) The investigator is required to maintain all correspondence with another investigator, an IRB, the sponsor, a
monitor, or FDA, including required reports;
ICH GCP 4.2.4 The investigator is required to ensure that all persons assisting with the trial are adequately informed about the protocol,
the investigational product(s), and their trial-related duties and function;
ICH GCP 8.3.11 The investigator is required to maintain all relevant communication (letters, meeting notes, notes of telephone calls) to
document any agreements or significant discussions regarding trial administration, protocol violations, trial conduct and AE reporting
[10] Document retention per protocol
[10] 21 CFR 312.62 (c) An investigator is required to retain trial records for a period of 2 years following the date a marketing application
is approved for the drug for the indication for which it is being investigated;
21 CFR 812.140 (d) An investigator or sponsor shall maintain the records required by this subpart during the investigation and for a
period of 2 years after the latter of the following two dates: The date on which the investigation is terminated or completed, or the date
that the records are no longer required for purposes of supporting a premarket approval application or a notice of completion of a product
development protocol;
ICH GCP 4.9.4 The investigator/institution is required to maintain the trial documents as required by the applicable regulatory
requirement(s). The investigator/institution
should take measures to prevent accidental or premature destruction of these documents;
ICH GCP 5.5.11 The sponsor-specific essential documents is required to 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. These documents should be
retained for a longer period, however, if required by the applicable regulatory
requirement(s) or if needed by the sponsor;
Drexel University Investigator Manual, Version 3/6/2014, 11/34,The investigator is required to maintain human research records,
including signed and dated consent documents for at least three years after completion of the research. Maintain signed and dated HIPAA
authorizations and consent documents that include HIPAA authorizations for at least seven years after completion of the research.
Drexel University, Record Management Program Master Schedule 5.1.14, 33/48 The investigator is required to maintain, if records
support a claim made in patents or a patent application, 30 years from completion of the research. All other records, should be kept 7
years from the later of (i) completion of the research or (ii) date of last third party request for such records. If a longer period is specified
in the protocol or associated agreement, such period should be used.
Drexel University, Record Management Program Master Schedule 5.1.14, 33/48 The investigator is required to maintain records of
human subject research, the longer of: 3 years after completion of the research, period specified in the protocol, period specified in the
associated agreement(s), or if research has FDA oversight, 2 years following the date a marketing application is approved for the drug for
the indication for
which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2
years after the investigation is discontinued and FDA is notified; if pediatric research, until the youngest subject turns twenty-five years
old. Sponsors should be notified prior to destruction. In addition, associated agreements should be reviewed for any
additional requirements.
Focused topic area
QA Support/Policy/Regulations
[1] Inspection of investigator's
records and reports
[1] 21 CFR 312. 68 and 21 CFR 812.45 Upon request from any properly authorized officer or employee of FDA, at reasonable times, an
investigator is requited to permit such officer or employee to have access to, and copy and verify any records or reports made by the
investigator. The investigator is not required to divulge subject names unless the records of particular individuals require a more detailed
study of the cases, or unless there is reason to believe that the records do not represent actual case studies, or do not represent actual
results obtained;
[2] Information indicating study
records fabricated/altered or
false/misleading reports prepared
and/or submitted or inadequate
supervision of study personnel who,
in turn, caused the above
[2] 21 CFR 312.70 and 21 CFR 812.119 After evaluating all available information, including any explanation presented by the
investigator, if the Commissioner determines that the investigator has repeatedly or deliberately failed to comply with the requirements,
or has repeatedly or deliberately submitted to FDA or to the sponsor false information in any required report, the Commissioner will
notify the investigator, the sponsor of any investigation in which the investigator has been named as a participant, and the reviewing
investigational review boards (IRBs) that the investigator is not eligible to receive test articles under this part. The notification to the
investigator, sponsor and IRBs will provide a statement of the basis for such determination. The notification also will explain that an
investigator determined to be ineligible to receive test articles under this part will be ineligible to conduct any clinical investigation that
supports an application for a research or marketing permit for products regulated by FDA, including drugs, biologics, devices, new
animal drugs, foods, including dietary supplements, that bear a nutrient content claim or a health claim, infant formulas, food and color
additives, and tobacco products.
Medical Device additional guidance
[1] Appropriate documentation
[2] ISO 14155:2011
ISO 14155:2011
Clinical investigation of medical
devices for human subjects - Good
clinical practice
[1] AAHRPP Element I.7.A. The Organization has and follows written policies and procedures to ensure that the use of any
investigational or unlicensed test article complies with all applicable legal and regulatory requirements when research involves
investigational or unlicensed test articles, the Organization confirms that the test articles have appropriate regulatory approval or meet
exemptions for such approval.
[2] Investigator qualified by education, training and experience;
IB to contain a summary of relevant manufacturing processes and related validation processes (and list of relevant standards complied
with);
There shall be an agreement between the sponsor and the principal investigator(s)/investigation site(s) and any other relevant parties;
The sponsor shall ensure documentation of training, experience and scientific or clinical knowledge for all the relevant parties involved in
order to adequately conduct the clinical investigation, including training, on
1.the use of the investigational device(s), 2.device accountability procedures (see 6.9), 3.IB, 4.CIP, 5.CRFs and instructions for
completion, 6.the written informed consent form and process as well as other written information provided to subjects, and 7.sponsor's
written procedures, this International Standard and any applicable regulatory requirements;
Adverse Event reporting to address the different failure modes of medical devices:
–Adverse Device Effect - insufficient or inadequate instructions for use, deployment, implantation, installation, or operation, or any
malfunction of the investigational medical device
–Device Deficiencies - inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or performance
–Adverse events not restricted to subjects – can also be users or other persons
Focused topic area
QA Support/Policy/Regulations
Children research
21 CFR 50.55 (e) (1) Where parental permission is to be obtained, the IRB may find that the permission of one parent is sufficient for
clinical investigations to be conducted under 50.51 (not involving greater than minimal risk) or 50.52 (involving greater than minimal risk
but presenting the prospect of direct benefit);
21 CFR 50.55 (e) (2) Where clinical investigations are covered by 50.53(involving greater than minimal risk and no prospect of direct
benefit, but likely to yield generalizable knowledge) or 50.54 (not otherwise approvable that present an opportunity to understand,
prevent, or alleviate a serious problem) and permission is to be obtained from parents, both parents must give their permission unless one
parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and
custody of the child;
21 CFR 50.55 (g) When the IRB determines that assent is required, it must also determine whether and how assent must be documented.
Financial aspects of the trial
ICH GCP 8.2.4 The investigator is required to document the financial agreement between the investigator/ institution and the sponsor for
the trial;
ICH GCP 8.2.4 The investigator is required to document that compensation to subject(s) for trial-related injury will be available;
FDA Payment to Research Subjects - Information Sheet. Guidance for Institutional Review Boards and Clinical Investigators. The IRB
should review both the amount of payment and the proposed method and timing of disbursement to assure that neither are coercive nor
present undue influence;
Drexel University, Policy: Gifts, Gift Cards, and Gift Certificates VI. SPECIAL PROCEDURE FOR CASH OR GIFT CARDS/GIFT
CERTIFICATES PURCHASED FOR HUMAN SUBJECT PAYMENTS IN CONNECTION WITH SPONSORED RESEARCH
ACTIVITY ONLY, 7. The PI is responsible for documenting the number of human subjects and the amount of payments to subjects.
Electronic records
21 CFR 11.10 Investigators who use closed systems to create, modify, maintain, or transmit electronic records is required to employ
procedures and controls designed to ensure the authenticity, integrity, and, when appropriate, the confidentiality of electronic records, and
to ensure that the signer cannot readily repudiate the signed record as not genuine;
21 CFR 11.10 (c) Electronic record procedures and controls is required to include protection of records to enable their accurate and ready
retrieval throughout the records retention period;
21 CFR 11.10 (i) Electronic record procedures and controls is required to include determination that persons who develop, maintain, or
use electronic record/electronic signature systems have the education, training, and experience to perform their assigned tasks;
21 CFR 11.10 (k) Electronic record procedures and controls is required to include systems documentation including: (1) Adequate
controls over the distribution of, access to, and use of documentation for system operation and maintenance; (2) Revision and change
control procedures to maintain an audit trail that documents time-sequenced development and modification of systems documentation.
Security of institutional data
Drexel University, Information and Resources Technology, Security of Information and Network Systems (IT-4) II All Institutional Data
residing on or copied from Enterprise Systems is considered confidential and is intended exclusively for purposes related to the
University's administration. All Institutional Data must be used only for the legitimate business of the University and specifically not for
commercial, personal and/or political purposes. Generally, departments and individuals should not have Protected Data on any Server.
Drexel University, Information and Resources Technology, End-User Device and Information Policy (IT-8) I Drexel University intends
to protect the confidentiality of educational, financial, health and other personal information provided to it and to protect information
created in the course of University business, education, research, and other activities in order to maintain sufficient protection of this data
on End-User Devices (any Mobile Device, computer, or storage system accessing, collecting, and/or storing data, regardless of the
ownership of the End-User Device);
Drexel University, Information and Resources Technology, Clinical Research Data Storage Policy (IT-6) II Personal computers, mobile
devices, media drives, and any other tools used for collecting, storing, and processing sensitive research data must be encrypted and
comply with the End-User Device and Information Security Policy (IT-8) and all of its applicable Information Security Requirements;
Drexel University, Information and Resources Technology, Email Policy (IT-7) III B Emails containing sensitive data must be encrypted
by approved University email encryption software before being sent over a network. All emails containing sensitive information must be
limited to minimum necessary information.
Focused topic area
QA Support/Policy/Regulations
Drexel University File Server
Drexel University, Information and Resources Technology, Acceptable Use Policy (IT-1) II Accounts are assigned to individuals and are
not to be shared unless specifically authorized by IRT. Each User is solely responsible for all functions performed from accounts assigned
to them. It is a violation of the AUP for any User to allow others (including other Users within the Drexel Network) to use or have access
to their account. It is a violation to use another User's account, with or without that person's permission. Intentionally or negligently
revealing one's password is prohibited. It is a violation to attempt to learn the password to another User's account, whether the attempt is
successful or not. The password used with an account, is the equivalent of an electronic signature. The use of User ID and password
authenticates an identity and gives on-line affirmations the force of a legal document;
Drexel University, Information and Resources Technology, Acceptable Use Policy (IT-1) III Users may not attempt to intercept, monitor,
forge, alter or destroy other Users' communications. Users may not infringe upon the privacy of others' computer or data. Users may not
read, copy, change, or delete another User's data or communications without the prior express permission of the owner;