INVESTIGATOR RESPONSIBILITIES

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INVESTIGATOR RESPONSIBILITIES

• April 2016

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Objectives

• Review and Discuss
• Responsibilities of the clinical research
  Investigator as per relevant regulations and
  guidelines.
• Responsibilities and commitments associated with
  signing the FDA Form 1572. (For non-IND studies,
  the DAIDS Investigator of Record Form applies
  instead of FDA Form 1572.)
• Financial disclosure requirements.
• Impact of protocol noncompliance.
• Oversight responsibilities related to the
  informed consent process, drug accountability,
  safety monitoring, maintaining essential study
  documents and delegation of responsibilities.

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Investigator Responsibilities
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What Does This Mean?

• The FDAs focus is on the Principal Investigator
  listed on FDA Form 1572.
• For DAIDS-funded trials, this is the Investigator
  of Record or (IoR).
• Others in the DAIDS structure/chain of command
  (such as the CTU PI or CRS Leader) will not be
  important at the time of the audit. It is the
  IoR who is answerable for the execution of the
  protocol.

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Investigator Responsibilities

• Ensure that the clinical investigation is
  conducted according to the approved protocol and
  in compliance with all relevant sections of the
  U.S. Code of Federal Regulations (CFR), ICH-GCP
  standards, and in-country regulations and
  guidelines.
• Protect the rights, safety and welfare of
  subjects.
• Control drugs, biological products and devices
  under investigation.

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Investigator Responsibilities Regulations and
Guidances

• Investigator responsibilities are specifically
  described in
• ICH E6 (Sections 4.0 and 8.0).
• U.S. Code of Federal Regulations (CFR).
• U.S. FDA Guidance Investigator Responsibilities
  (October 2009).
• U.S. FDA Guidance QA Form FDA 1572 (May 2010).
• FDA Form 1572 / DAIDS IoR Form.

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ICH E6 Good Clinical PracticeConsolidated
Guideline
Objective to provide a unified standard for the
EU, Japan, U.S. to facilitate mutual acceptance
of clinical data by the regulatory authorities
Published as official guidance in U.S. Federal
Register in 1997
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ICH E6 GCP Section 4.0 Investigator
Responsibilities
Investigators Qualifications and Agreements
Informed Consent of Trial Subjects
4.1
4.8
Adequate Resources
Records and Reports
4.2
4.9
Medical Care of Trial Subjects
Progress Reports
4.3
4.10
Communications with IRB/IEC
Safety Reporting
4.4
4.11
Compliance with Protocol
Premature Termination or Suspension of a Trial
4.5
4.12
Investigational Product(s)
Final Report(s) by Investigator
4.6
4.13
Randomization Procedures and Unblinding
4.7
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Country-Specific Requirements

• This presentation reviews the U.S. federal
  requirements for the clinical Investigator.
• All local and country-level requirements must
  also be met.
• Contact your local IRB/IEC or CTU PI for
  additional information on these.

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FDA Clarification of Investigator
Responsibilities

• Supervision of the conduct of the clinical
  investigation.
• Delegation of tasks to study staff.
• Training of study staff.
• Supervision of staff to whom tasks are delegated.
• Reporting protocol deviations.

• Supervision of third parties (if applicable).
• Protection of the rights, safety and welfare of
  participants in clinical trials.
• Provision of reasonable medical care.
• Provide reasonable access to medical care.

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Review of FDA Form 1572
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Form FDA 1572

• Include screen shot here.

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By Signing Form 1572

• The Investigator is agreeing that he or she will
  personally conduct or supervise the described
  investigations.
• To do this, the Investigator must be intimately
  involved with the study. Depending on the size of
  the staff, the qualifications of the staff
  members, and the complexity of the protocol(s),
  this involvement may vary according to the site
  and protocol.
• The Investigator must have a full understanding
  of the protocol, as well as stay informed of all
  participant and site issues.
• The Investigator should ensure procedures are
  established to escalate issues quickly when
  needed.

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FDA Form 1572Eight Investigator Commitments

• Maintain protocol adherence
• Personally conduct or supervise
• Ensure informed consent of subjects
• Report adverse experiences

• Provide training to sub-investigators
• Ensure adequate and accurate recordkeeping
• Ensure proper IRB/IEC review and reporting
• Comply with all regulatory requirements

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Who Should be Listed as a Sub-Investigator on the
1572?

• The decision to list an individual as a
  sub-investigator depends on his/her level of
  responsibility-- whether he/she is performing
  significant clinical, investigation-related
  duties.
• In general, if an individual is directly involved
  in the performance of procedures required by the
  protocol, and the collection of data, that person
  should be listed on the 1572.
• It is not necessary to include someone with only
  an occasional or ancillary role.

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When to Update the 1572(U.S. Federal Regulation)

• According to U.S. federal regulation, the FDA
  Form 1572 must only be updated when a new
  protocol has been added to the IND or a new
  Investigator is added to the study. However,

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When to Update the 1572(DAIDS Protocol
Registration Manual)

• Within 30 days of any change in information, such
  as
• The Investigator of Record changes.
• A sub-investigator is added to the study or
  removed.
• At the time of continuing IRB/IEC review
• (if required by the local IRB/IEC).
• A laboratory is added, removed or changed.
• Site location added, removed or changed.

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Investigator of Record Form

• Insert page 1 of Investigator of Record Form

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Requirement for Investigators and
Sub-Investigators to File Financial Disclosure
Forms
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Reporting Financial Interests

• Goal preserve objectivity of clinical research
  and the protection of human subjects
• Regulation 21 CFR 54
• Requirement each clinical investigator must
  disclose any financial interests that may be
  affected by the outcome of the research or attest
  to the absence of relevant significant financial
  interests

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Specific Requirement

• Per 21 CFR 54, each clinical research
  Investigator and sub-investigator (anyone listed
  on the FDA Form 1572 for the study) is required
  to disclose the aggregated financial interests of
  themselves, their spouse and dependent children,
  as they relate to the study sponsor and/or study
  product(s).
• Per 21 CFR 312.53, financial disclosures must be
  completed prior to study involvement.

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Demonstrating Compliance

• Individual FD forms must be completed, signed and
  dated before the relevant1572 form, to which the
  investigator/sub-investigator is being added, is
  finalized, signed and dated.
• The 1572 must be finalized, signed, and dated
  before the Investigator or sub-investigator adds
  their signature and start date to the DoA.
• Note The Investigators or
  sub-investigators DoA start date must be no
• sooner than the signature dates
  on their FD and corresponding 1572.

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When to Report 4 Time Points

• Before an Investigator or sub-Investigator begins
  study activities (i.e., before final sign off by
  the IoR on the 1572 or DAIDS IoR Form).
• Within thirty (30) days of discovering that
  relevant changes to their significant financial
  interests have occurred (during their study
  involvement and for one year following the end of
  their study involvement).
• (continued on next slide)

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When to Report 4 Time Points

• 
  (continued from last
  slide)
• When an Investigator or Sub-Investigator is
  removed from the FDA Form 1572 prior to study
  completion.
• At the completion of all study-specific
  activities, that is, the date of the last
  follow-up for the study at that site.

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How to Report Financial Disclosure

• A study-specific, Financial Disclosure Form can
  be found on the MTN website (www.mtnstopshiv.org)
  - Study Implementation Materials.
• Definition of reportable financial interests (as
  per 21 CFR 54) and instructions for completion of
  the form will appear with the form.

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Steps to Report Financial Disclosure

• Print the study-specific, Financial Disclosure
  Form from www.mtnstopshiv.org.
• Complete the form remember to sign and (hand)
  date it.
• Upload a scanned copy of the completed, signed
  and dated form to the the DAIDS Protocol
  Registration System.
• File the original, completed, signed and dated
  form in the study binder with the associated 1572
  form.

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How are Conflicts Managed?

• All financial disclosure statements will be
  reviewed by the MTN Leadership Operations
  Center (LOC).
• If potential conflicts of interest are
  identified, the LOC, in conjunction with the
  Investigator, will determine if steps need to be
  taken to minimize the potential for bias.

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ICH E6 Section 4.0 Investigator
Responsibilities
Investigators Qualifications and Agreements
Informed Consent of Trial Subjects
4.1
4.8
Adequate Resources
Records and Reports
4.2
4.9
Medical Care of Trial Subjects
Progress Reports
4.3
4.10
Communications with IRB/IEC
Safety Reporting
4.4
4.11
Compliance with Protocol
Premature Termination or Suspension of a Trial
4.5
4.12
Investigational Product(s)
Final Report(s) by Investigator
4.6
4.13
Randomization Procedures and Unblinding
4.7
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Compliance with the Protocol

• ICH E6 Section 4.5
• FDA Form 1572
• 21 CFR 312.60
• 21 CFR 812.100

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Protocol Compliance

• The Investigator is expected to make every effort
  to ensure that the trial is conducted in
  compliance with the protocol approved by the
  IRB/IEC.
• The IoRs dated signature on the protocol
  signature page confirms this agreement.

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Protocol Compliance

• The Investigator agrees that he or she will not
  make any changes in the research without IRB/IEC
  approval, except where necessary to eliminate
  apparent immediate hazards to human subjects
  (see FDA Form 1572).

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Protocol Compliance

• Any departure from the protocol must be
  documented as a protocol deviation.
• In the event you find a deviation has occurred at
  your site, follow the instructions provided to
  you in the DAIDS Source Documentation policy, the
  Protocol SSP and by the FHI 360 CRM for
  documenting deviations and making corrections.

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Deviations from the Protocol

• Recognizing that protocol deviations do sometimes
  occur, it is important to promptly document and
  report them.
• Why is it critical that this happens?

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Potential Impact of Noncompliance

• Impact on risk to the participant
• Impact on data quality
• Impact on scientific integrity and credibility
• Rejection of data by regulatory bodies
• Selection of the site for FDA Inspection
• Disqualification of the Investigator
• Suspension of site activities

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Risks for Noncompliance

• Insufficient investigator involvement/oversight
  in study conduct.
• Poor supervision and training of study staff.
• Inappropriate delegation of study tasks to
  unqualified persons.
• Overworked investigator and study staff (e.g.,
  too many subjects, complex study with large data
  collection, too many concurrent studies).
• Failure to adequately protect study subjects.

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ICH E6 Section 4.0Investigator
Responsibilities
Investigators Qualifications and Agreements
Informed Consent of Trial Subjects
4.1
4.8
Adequate Resources
Records and Reports
4.2
4.9
Medical Care of Trial Subjects
Progress Reports
4.3
4.10
Communications with IRB/IEC
Safety Reporting
4.4
4.11
Compliance with Protocol
Premature Termination or Suspension of a Trial
4.5
4.12
Investigational Product(s)
Final Report(s) by Investigator
4.6
4.13
Randomization Procedures and Unblinding
4.7
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Role of the Investigator in Ensuring Informed
Consent and Some Consenting Challenges

• Declaration of Helsinki
• ICH E6 Section 4.8
• FDA Form 1572
• 21 CFR 50

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The Consenting Process
Discuss study, risk/benefits, etc.
Provide informed consent form
Update participants
Assess understanding and willingness
Allow time for understanding
Ensure comprehension
Encourage questions
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Key Points of the Informed Consent Process
Translation
Role of the witness
Timing
Signing/Dating
Version
Re-signing the consent
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Consenting a Vulnerable Population Illiterate
Participants

• What are the consenting challenges?
• What strategies could you use to mitigate
  challenges?

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Illiterate Participants

• Consider asking potential participants to read
  the informed consent form (ICF) out loud.
• Test writing skills.
• Read the informed consent form to the
  participant.
• Ask participant to teach back.

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ICH E6 Section 4.0Investigator
Responsibilities
Investigators Qualifications and Agreements
Informed Consent of Trial Subjects
4.1
4.8
Adequate Resources
Records and Reports
4.2
4.9
Medical Care of Trial Subjects
Progress Reports
4.3
4.10
Communications with IRB/IEC
Safety Reporting
4.4
4.11
Compliance with Protocol
Premature Termination or Suspension of a Trial
4.5
4.12
Investigational Product(s)
Final Report(s) by Investigator
4.6
4.13
Randomization Procedures and Unblinding
4.7
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Investigational Study Product(s)

• ICH E6 Section 4.6
• 21 CFR 312.57(a)
• 21 CFR 312.62(a)

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Investigational Study Product

• Responsibility for investigational product
  accountability lies with the Investigator/institut
  ion.
• Some or all of these duties can be delegated to
  the pharmacist or other individual who is under
  the supervision of the Investigator.
• The product should be stored as specified by the
  sponsor and in accordance with regulatory
  requirements.

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Investigational Study Product

• Investigator or designee should ensure products
  are only used in accordance with the approved
  protocol.
• The Investigator or designee should explain the
  correct use of the product and should check
  throughout the trial that each participant is
  following instructions properly.

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Product Accountability Records

• These records should include the following
  information
• Product delivery to the trial site.
• Inventory at the site.
• Proper storage.
• Use by each subject.
• Return to the sponsor or alternative disposition
  of unused product.
• Dates, quantities, batch/serial numbers,
  expiration dates (if applicable), unique code
  assigned to the product and trial participant.

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ICH E6 Section 4.0Investigator
Responsibilities
Investigators Qualifications and Agreements
Informed Consent of Trial Subjects
4.1
4.8
Adequate Resources
Records and Reports
4.2
4.9
Medical Care of Trial Subjects
Progress Reports
4.3
4.10
Communications with IRB/IEC
Safety Reporting
4.4
4.11
Compliance with Protocol
Premature Termination or Suspension of a Trial
4.5
4.12
Investigational Product(s)
Final Report(s) by Investigator
4.6
4.13
Randomization Procedures and Unblinding
4.7
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Medical Care of Trial Subjects and Safety
Reporting

• ICH E6 Sections 4.3 and 4.11
• DAIDS Expedited Adverse Events Reporting Policy,
  DWD-POL-CL-013.03

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Medical Care of Trial Subjects

• A qualified physician must be responsible for all
  trial-related medical decisions and ensure
  medical care is provided for any AEs while in the
  trial.
• It is recommended that the Investigator inform
  the participants primary physician about trial
  participation, if the participant agrees.
• The Investigator should attempt to find the
  reason for premature withdrawal of participation
  in the trial when appropriate.

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Safety Reporting

• AEs should be reported according to the
  requirements of the protocol.
• All SAEs should be reported to DAIDS per the EAE
  Reporting Manual. PTIDs (not names or other
  unique identifiers) should be used in these
  reports.
• Investigator must follow the sites IRB/IEC
  requirements regarding reporting AEs, EAEs, SAEs
  and unanticipated problems to the IRB/IEC.

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ICH E6 Section 4.0Investigator Responsibilities
Investigators Qualifications and Agreements
Informed Consent of Trial Subjects
4.1
4.8
Adequate Resources
Records and Reports
4.2
4.9
Medical Care of Trial Subjects
Progress Reports
4.3
4.10
Communications with IRB/IEC
Safety Reporting
4.4
4.11
Compliance with Protocol
Premature Termination or Suspension of a Trial
4.5
4.12
Investigational Product(s)
Final Report(s) by Investigator
4.6
4.13
Randomization Procedures and Unblinding
4.7
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Essential Documents

• ICH E6 Section 4.9 and 8.0

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Essential Study Documents

• ICH-GCP Section 8.0 provides a clear presentation
  of those documents required to be kept on-file at
  the Clinical Research Site (CRS) by the
  Investigator of Record.
• These documents, individually and collectively,
  permit evaluation of the conduct of the trial and
  the quality of the data produced.

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Essential Study Documents

• Filing essential documents at the CRS in a timely
  manner can greatly assist in the successful
  management of a trial by the Investigator.
• These documents may be audited by the sponsor's
  independent audit function and inspected by
  regulatory authorities.

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ICH E6 Section 4.0Investigator
Responsibilities
Investigators Qualifications and Agreements
Informed Consent of Trial Subjects
4.1
4.8
Adequate Resources
Records and Reports
4.2
4.9
Medical Care of Trial Subjects
Progress Reports
4.3
4.10
Communications with IRB/IEC
Safety Reporting
4.4
4.11
Compliance with Protocol
Premature Termination or Suspension of a Trial
4.5
4.12
Investigational Product(s)
Final Report(s) by Investigator
4.6
4.13
Randomization Procedures and Unblinding
4.7
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Site Oversight
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How is Oversight Assessed?

• Were those to whom tasks were delegated qualified
  to do the tasks?
• Did staff received adequate training to perform
  the delegated tasks?
• Is there evidence demonstrating the ongoing
  involvement of the IoR?
• Was there adequate supervision of any third
  parties?

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Demonstrating Adequate Oversight

• Availability of sub-investigator CVs and clinical
  licenses.
• Maintenance of staff training records.
• Timely signature/initials/date of IoR on study
  documents.
• Delegation of Authority Log (DoA).
• Complete and accurate study product
  accountability records.

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Study Delegation of Authority Log (continued
on next slide)

• Insert page 1 of study Delegation of Authority
  Log (DoA)

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(No Transcript)
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DoA Best Practices

• Names should be printed legibly or typed,
  signatures and initials must be handwritten.
• When staff roles and/or responsibilities change,
  add an end date and IoR initials/date to the
  current line listing, and add the staff member to
  a new line and list all responsibilities with the
  new start date and IoR initial/date
• In the case where the DoA includes a list of
  staff from multiple clinical research sites
  (CRSs) as members of a single clinical trials
  unit (CTU), staff who are primary to the site
  should be distinguished from staff who are listed
  in back-up/coverage? roles.

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Summary of Required Pre-activation Regulatory
Submissions
63
References

• ICH E6
• U.S. FDA Form 1572
• DAIDS IoR Form
• U.S. Code of Federal Regulations (CFR)
• U.S. FDA Guidance Investigators
  Responsibilities, (October 2009)

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References

• U.S. FDA Guidance QA Form FDA 1572 (May 2010)
• DAIDS Policy Requirements for Source
  Documentation, DWD-POL-CL-04.00 and
  DWD-POL-CL-04.00A1
• DAIDS Expedited Adverse Events Reporting Policy,
  DWD-POL-CL-013.03