Youre In Charge: Investigator Responsibilities

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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.)
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Exposures Disclosures

• I have the following financial relationships to
  disclose
• 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,

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Youre In Charge InvestigatorResponsibilities
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Youre In Charge InvestigatorResponsibilities
It sounds really boring, but it can keep you
in your job
and
out of jail.
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Question 1
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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

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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

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Question 2
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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
  guidelines
• It is not IHC (immunohistochemistry)!

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Code of Federal Regulations

• Responsibilities of Sponsors and Investigators
  312.50
• General responsibilities of investigators 312.60
• Control of the investigational agent 312.61
• Investigator recordkeeping and record retention
  312.62
• Investigator reports 312.64
• Assurance of IRB review 312.66
• Inspection of investigators records and reports
  312.68
• Handing of controlled substances 312.69
• Disqualification of a clinical investigator 312.70

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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
  Sponsor-Investigator.
• 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.

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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
  regulations
• Control of all drugs/agents/devices under
  investigation
• For protecting the rights, safety, and welfare of
  subjects under the investigators care

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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
  product(s)
• Interested in the scientific aspects of the trial

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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

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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

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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
  it.

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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.

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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

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CONFIDENTIAL
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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
  information
• 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

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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

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Question 3
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Informed Consent

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

NEJM348, 721, 2003
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Informed Consent

• Must be signed and personally dated by the
  subject AND the individual who conducted the
  discussion
• 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
  situations
• If subject and legal representative are unable to
  read, an impartial witness must be present and
  sign the ICF

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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
  initialling
• Do not use white out
• Do not scribble out words

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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
  protocol.
• 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
  form.

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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,
  return/destruction
• 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.

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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

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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

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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.

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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
  information

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Question 4
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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

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Question 5
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Investigator Reports

• Adverse Event/Safety reporting
• Serious Adverse Event (SAE) any untoward
  medical occurrence that meets one or more of the
  following
• 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,
  etc.

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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
  severe
• NCI Expedited reporting guidelines
  http//ctep.cancer.gov/forms/NCI_AEReporting_Gdln_
  final.pdf

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Question 6
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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
  relationship
• Not-related, unlikely, possible, probable,
  definite
• NCI Expedited reporting guidelines
  http//ctep.cancer.gov/forms/NCI_AEReporting_Gdln_
  final.pdf

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Question 7
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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
  institution
• Only members who are independent of the
  investigator sponsor can vote or provide an
  opinion

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Assurance of Institutional Review Board (IRB)
Review

• 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.
  advertisements)

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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.

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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.

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Quality Assurance

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

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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
  requirements
• 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

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Quality Assurance

• Major deviations (NCI US definitions)
• A protocol variance that makes the resulting data
  questionable
• 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

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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
  liability

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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
  results

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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

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Conflict of Interest

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

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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

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Youre In Charge

• Running a clinical trial can be complex
• You will need full support from your research
  team
• 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

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So You Think Youre In Charge!
We Are Just Insects on the Windshield of Life!
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So You Think Youre In Charge!
Unfortunately We Live in the Real World!
Material Transfer Agreements
Fiscal Responsibility
Tech Transfer
Confidentiality Agreements
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Is Anyone Still Awake?
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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.

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CONFIDENTIAL
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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
  study
• Personally conduct or supervise the study

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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)

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CONFIDENTIAL
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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

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CONFIDENTIAL
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Source Document Requirements
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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
  retention
• Disposition of Drug- dates, quantities and use by
  subjects
• Case Histories- must be adequate and accurate
• Retain records- 2 years following date of NDA
  approval or 2 years after the investigations is
  terminated

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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

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CONFIDENTIAL
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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

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• GCP Overview / Regulatory Requirements

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