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Youre In Charge: Investigator Responsibilities


(I am not sure why he is not doing it this year, but I have been ... Do not scribble out words. Investigator Recordkeeping and Record Retention. Case Histories ... – PowerPoint PPT presentation

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Title: Youre In Charge: Investigator Responsibilities

Youre In Charge InvestigatorResponsibilities
  • Merrill J. Egorin, M.D.
  • University of Pittsburgh Cancer Institute

Modified slightly from the 2007 talk given
by Stephen M. Hahn Department of Radiation
Oncology University of Pennsylvania Philadelphia,
PA (I am not sure why he is not doing it this
year, but I have been told that no one should
have to do this talk more than once.)
Exposures Disclosures
  • I have the following financial relationships to
  • Consultant for Novartis, Bristol-Myers Squibb,
    Saladax, Amplimed, Adherex
  • Grant/Research support from Novartis,
    Bristol-Myers Squibb, , Merck, The NCI
  • Honoraria from Novartis, Bristol-Myers Squibb,

Youre In Charge InvestigatorResponsibilities
Youre In Charge InvestigatorResponsibilities
It sounds really boring, but it can keep you
in your job
out of jail.
Question 1
What is Good Clinical Practice (GCP)?
  • An international ethical and scientific standard
    for the design, conduct, performance, monitoring,
    auditing, recording, analyses, and reporting of
    clinical trials that involve participation of
    human subjects

Good Clinical Practice
  • Compliance with GCP
  • Provides public assurance that the rights,
    safety, and well-being of subjects are protected
    consistent with the Declaration of Helsinki
  • Provides public assurance that the results data
    from the clinical trial are credible

Question 2
International Conference on Harmonization (ICH)
of GCP (1996)
  • Unified standard incorporating the GCPs of the
    US, EU, Japan, Canada, Australia, Scandinavia,
    and the WHO
  • Facilitates the mutual acceptance of clinical
    trial data when studies are performed under these
  • It is not IHC (immunohistochemistry)!

Code of Federal Regulations
  • Responsibilities of Sponsors and Investigators
  • General responsibilities of investigators 312.60
  • Control of the investigational agent 312.61
  • Investigator recordkeeping and record retention
  • Investigator reports 312.64
  • Assurance of IRB review 312.66
  • Inspection of investigators records and reports
  • Handing of controlled substances 312.69
  • Disqualification of a clinical investigator 312.70

Who is a Principal Investigator (PI)?
  • The 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 is usually
    called the principal investigator.
  • If a trial does not have a sponsor, the PI is the
  • Any individual member of the clinical trial team
    designated and supervised by the investigator at
    a trial site to perform critical trial-related
    procedures and/or to make important trial-related
    decision (e.g. associates, residents, fellow)
    are, under the regulations, considered
    sub-investigators, not PIs or CO-investigators.

General Responsibilities of Investigators
  • An investigator is responsible for
  • Ensuring that an investigation is conducted
    according to
  • Signed investigator statement (FDA 1572)
  • Study protocol
  • IRB requirements
  • All applicable federal, state, institutional
  • Control of all drugs/agents/devices under
  • For protecting the rights, safety, and welfare of
    subjects under the investigators care

Qualifications for Investigators
  • Qualified by education, training, experience to
    assume proper conduct of the trial
  • Aware of comply with GCP
  • Familiar with the use of investigational
  • Interested in the scientific aspects of the trial

Qualifications for Investigators
  • Have adequate time to
  • Discuss, read approve protocol
  • Identify recruit subjects
  • Properly assess follow subjects
  • Have adequate personnel resources to conduct
    the trial
  • Able to meet the recruitment targets
  • Conduct the trial in compliance with the protocol
    without deviation

Qualifications for Investigators
  • Maintain a list of research team members to whom
    trial-related duties have been delegated
  • Keep research team members well informed about
    the trial at all times
  • Permit monitoring, auditing inspection by
    sponsors regulatory authorities

Control of Investigational Drug/Agent/Device
  • An investigator shall distribute the
    drug/agent/device only to subjects under the
    investigators personal supervision or under the
    supervision of a sub-investigator responsible to
    the investigator
  • The investigator shall not supply the
    investigational drug/agent/device to any person
    not authorized by the investigator to receive

Consent of Subjects
  • An investigator must, in accordance with part 50
    of the Code of Federal Regulations, obtain the
    informed consent of each human subject to whom
    the drug/agent/device is distributed.
  • Note informed consent is more than handing
    the subject a form. It is a process.

Informed Consent
  • A process by which a subject voluntarily
    confirms his or her willingness to participate in
    a particular trial, after having been informed of
    all aspects of the trial that are relevant to the
    subjects decision to participate.
  • ICH Guideline for GCP 1.28

Informed Consent Process
  • Intended to
  • Give a subject all the information he or she
    reasonably would want about a study
  • Ensure that the subject understands this
  • Give the subject time to consider whether or not
    they want to participate
  • Allow the subjects to ask questions of the
    investigator, staff, etc. Investigator must
    answer all questions
  • Provide protections for vulnerable subjects

Informed Consent
  • Must comply with GCPs, local and IRB
    requirements, 21 CRF, ICH Guidelines, and
    Declaration of Helsinki
  • Must be approved by IRB prior to use
  • Must be understandable to the subject
    (Non-technical and in the subjects own language)
  • May not cause subject to waive legal rights

Question 3
Informed Consent
  • Must be understandable to the subject
    (Non-technical and in the subjects own language)

NEJM348, 721, 2003
Informed Consent
  • Must be signed and personally dated by the
    subject AND the individual who conducted the
  • Subject must receive a copy of the informed
    consent document
  • Subjects legally authorized representative can
    sign for subject if subject is not able to read,
    not able to understand, or in emergency
  • If subject and legal representative are unable to
    read, an impartial witness must be present and
    sign the ICF

Investigator Recordkeeping and Record Retention
  • Case Report Form (CRF) a printed or electronic
    document designed to record protocol-required
    information on each subject
  • Source Document may include hospital records,
    clinical and office charts, lab reports, subject
    diaries, etc
  • Investigator should ensure the accuracy,
    completeness, timeliness of data in CRFs
  • Data in the CRFs must be consistent with and
    verifiable with the source documents
  • Correct data in the CRF by striking out and
  • Do not use white out
  • Do not scribble out words

Investigator Recordkeeping and Record Retention
  • Case Histories
  • Prepare and maintain adequate and accurate case
    histories that record all observations and other
    data pertinent to the study on each individual
    distributed to or employed as a control on the
  • CRF, supporting data, signed consent forms,
    medical records, progress notes, hospital charts,
    nurses notes
  • Case histories should document that informed
    consent was obtained prior to the subjects
    participationthis is in addition to the consent

Investigator Record Keeping and Retention
  • Disposition of drug/agent/device
  • Maintain adequate records of the disposition of
    all drugs/agents/devices
  • Dates, quantity, subject use, shipping, storage,
  • Record Retention
  • Retain records for a period of 2 years following
    the date a drug/agent/device is approved for the
    indication in which it is being investigated or
    if no application is filed/approved, 2 years
    after the investigation is discontinued and FDA
    is notified.

Maintenance of a Study Binder for Every Protocol
  • List of all study personnel
  • Their initials signatures
  • Their qualifications responsibilities
  • Dates of their participation
  • Up-to-date, signed, dated CVs for staff who
  • Undertake consent assessments of subjects
  • Make entries in case report forms (CRFs)
  • Up-to-date licenses of laboratories providing
    test results and their normal ranges

Investigator Reports
  • Progress Reports
  • - Sending reports to the sponsor as required by
    the protocol.
  • - Sponsor-investigators are required under
    312.33 to submit annual reports to FDA on the
    progress of the clinical investigation.
  • Safety Reports
  • - Promptly report to the sponsor any adverse
    effect that may reasonable be regarded as caused
    by, or probably cause by, the drug/agent/device.
  • Sponsor-investigators are required to report
    adverse effects that are both serious and
    unexpected and/or deaths directly to FDA in
    accordance with 312.32

Investigator Reports
  • Final Report
  • Provide the sponsor/FDA (for sponsor-investigators
    ) with an adequate report shortly after
    completion of the investigation.
  • Financial Disclosure Reports
  • Provide sponsor with sufficient accurate and
    current financial information to allow for
    accurate certification/disclosure as required
    under part 54.

Investigator Reports
  • New information
  • New information available during the course of
    the trial must be passed along to the IRB
  • If the new information is relevant to the
    subjects participation, consent form must be
    updated approved by the IRB
  • For subjects already on study, provide the new
    information at their next visit or sooner if
    there is a risk to the patient or if consent is
    likely to be revoked
  • Current subjects should be re-consented with
    the new IRB-approved consent form
  • Delay accrual until IRB approval of new

Question 4
Investigator Reports
  • Adverse Event/Safety reporting
  • Adverse Event (AE) any untoward medical
    occurrence in a trial subject, which does not
    necessarily have a causal relationship with the
    study treatment

Question 5
Investigator Reports
  • Adverse Event/Safety reporting
  • Serious Adverse Event (SAE) any untoward
    medical occurrence that meets one or more of the
  • Results in death
  • Is life-threatening
  • Requires inpatient hospitalization or
    prolongation of an existing hospitalization
  • Is a congenital anomaly or birth defect
  • Is a medically significant event, for any reason,
    these might include pregnancy, cancer, overdose,

Investigator Reports
  • Adverse Event/Safety reporting-Questions to ask
  • Is the event unexpected?
  • Reported in the Investigators Brochure
  • Known events that have become more frequent or
  • NCI Expedited reporting guidelines

Question 6
Investigator Reports
  • Adverse Event/Safety reporting-Questions to ask
  • Is the event treatment-related?
  • Reasonable causal relationship to be determined
    based upon prior experience with treatment
  • If an association cannot be ruled out, then it
    should be considered to have a reasonable
  • Not-related, unlikely, possible, probable,
  • NCI Expedited reporting guidelines

Question 7
Institutional Review Board (IRB)
  • A reasonable number of members who collectively
    have the qualifications experience to review
    evaluate the science, medical aspects, and ethics
    of the proposed trial
  • At least 5 members
  • At least 1 non-scientific member
  • At least 1 member who is independent of the
  • Only members who are independent of the
    investigator sponsor can vote or provide an

Assurance of Institutional Review Board (IRB)
  • Before initiating a trial, written IRB approval
    of the following documents is needed
  • Trial protocol, investigator brochure
  • Any amendments
  • Written informed consent form
  • Any other written information to be provided to
    study subjects
  • Any subject recruitment procedures (i.e.

Assurance of IRB Review
  • The PI should assure that an IRB that complies
    with all the requirements set forth in part 56
    will be responsible for the initial and
    continuing review and approval of the study.
  • 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.
  • 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.
  • Yes, the PI is responsible for making sure
    the IRB meets all federal regulations and follows
    all applicable regulations during the course of
    his/her investigation.

Inspection of Investigators Records and Reports
  • Upon request from any properly authorized officer
    or employee of FDA, permit the officer or
    employee to have access to, copy and verify any
    records or reports made by the investigator.
  • Not required to divulge subject names unless the
    records of the particular individual require a
    more detailed study of the cases or there is
    reason to believe that the records do not
    represent the actual case studies/results.

Quality Assurance
  • Sponsor
  • Responsible for implementing and maintaining
    quality assurance for the trial, in compliance
    with the protocol, GCP, and regulatory
  • Can be governmental agencies, foundations,
    pharmaceutical industries for funded studies
  • Can be the institution conducting the study
  • Investigator-sponsored studies

Quality Assurance
  • Monitoring
  • The act of overseeing the progress of a clinical
    trial, and ensuring that it is conducted,
    recorded, and reported in accordance with the
    protocol, GCP, and applicable regulatory
  • Auditing
  • A systematic and independent examination of
    trial-related activities and documents to
    determine whether they adhere to protocol, GCP,
    and the applicable regulatory requirements

Quality Assurance
  • Major deviations (NCI US definitions)
  • A protocol variance that makes the resulting data
  • Consent form signed after patient started therapy
  • Treatment which is not part of the protocol
  • Failure to report SAE
  • Minor Deviations
  • Deviations that do not affect the outcome or
    interpretation of the study and do not fulfill
    the criteria for major deviations

Research Misconduct
  • Research misconduct does not include honest
    errors or honest differences of opinion
  • From S. Woollen, Associate Director for
    Bioresearch Monitoring, FDA, 2003
  • If FDA has information indicating that an
    investigator or sponsor-investigator has
    repeatedly or deliberately failed to comply with
    the requirements identified in these parts of the
    Code of Federal Regulations or has submitted
    false information to FDA or a sponsor s/he may be
    disqualified and be subject to criminal and civil

Data Analysis Reporting
  • As a principal investigator, you should
  • Have access to the full and raw data
  • Have control over how the data are analyzed
  • Have the right to publish the results
  • Sponsors reserve the right to review a manuscript
    for a defined period, but must impose no
    impediment on publication of the trials full

Conflict of Interest
  • Disclosure of financial or other interests that
    might be construed as resulting in an actual,
    potential, or apparent conflict, is important to
    maintain the confidence of physicians, patients,
    and the general public, in the integrity of
    clinical cancer research

Conflict of Interest
  • Many institutions have their own conflict
  • Universities
  • Cooperative groups
  • ASCO policy (2002) requires disclosure of
  • Employment or leadership position
  • Advisory role
  • Stock ownership
  • Honoraria
  • Research funding
  • Expert testimony
  • http//

Conflict of Interest
  • Recent update of ASCO guidelines
  • Clarified definition of PI
  • Refinement of restrictions on non-PIs
  • Time period for restrictions
  • Expansion of PI exceptions
  • J Clin Oncol 24517, 2006

Youre In Charge
  • Running a clinical trial can be complex
  • You will need full support from your research
  • You will need to be careful and stringent on
    every trial-related issue
  • You will need to protect the rights and integrity
    of your trial subjects
  • And you need to recognize the realities
    illustrated on the next 2 slides

So You Think Youre In Charge!
We Are Just Insects on the Windshield of Life!
So You Think Youre In Charge!
Unfortunately We Live in the Real World!
Material Transfer Agreements
Fiscal Responsibility
Tech Transfer
Confidentiality Agreements
Is Anyone Still Awake?
Good Clinical Practice
  • Good Clinical Practice (GCP) is an
    international ethical and scientific quality
    standard for designing, conducting, recording,
    and reporting trials that involve the
    participation of human subjects.

Investigator Obligations
  • The investigator is responsible for ensuring that
    a clinical trial is conducted according to
  • The PI is ultimately responsible for the study.
  • Applicable international regulations such as
    ICH-GCP, the Declaration of Helsinki, and the
    Code of Federal Regulations
  • The Protocol
  • Applicable local regulations
  • Requirements of Institutional Review Board (IRB)
  • Read and understand the Investigators Brochure
    (potential risks and side effects)
  • Obtain IRB approval and continuing review of the
  • Personally conduct or supervise the study

Investigator Obligations
  • Allow inspection by regulatory authorities
  • Obtain and documents Informed Consent for every
    Subject PRIOR to study participation
  • Maintain adequate and accurate records (CRFs
    Source documents, and IP disposition records)
  • Document and explain any protocol deviation
  • Report Adverse Events as required by the IRB
  • Ensure that all study personnel understands their
    obligations to meet all of the above (Maintain a
    list of delegated responsibilities)

Sponsor Obligations
  • Select qualified investigators by their
    education, training, and experience
  • Provide information to conduct the study
  • Provide an Investigator Brochure
  • Communicate changes to the study
  • Monitor the study
  • Audit the study
  • Notify appropriate authorities and
    investigational sites of new adverse effects or
    risks with respect to the drug
  • Keep records of drug disposition
  • Collect financial disclosure information

Source Document Requirements
FDA Facts about Source Documentation
  • FDA Requirements Related to Source Documents in
    clinical trials
  • IND Regulations 21 CFR 312
  • 312.62 Investigator recordkeeping and record
  • Disposition of Drug- dates, quantities and use by
  • Case Histories- must be adequate and accurate
  • Retain records- 2 years following date of NDA
    approval or 2 years after the investigations is

FDA Facts about Source Documentation
  • FDA Requirements Related to Source Documents in
    clinical trials
  • 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 investigations on each
    individual administered the investigational drug
    or employed as a control

FDA Facts about Source Documentation
  • FDA Requirements Related to Source Documents in
    clinical trials
  • 312.62 (b) cont..- Case Histories include
  • Case report form and supporting data including,
    for example,
  • Signed and dated consent forms and
  • Medical records, for example
  • progress notes of the physician
  • individuals hospital chart(s)
  • nurses notes

  • GCP Overview / Regulatory Requirements

So You Think Youre In Charge!
We Are Just Insects on the Windshield of Life!
So You Think Youre In Charge!
We Are Just Insects on the Windshield of Life!
So You Think Youre In Charge!
We Are Just Insects on the Windshield of Life!
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