The Role of the Investigator in Clinical Research

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The Role of the Investigator in Clinical Research

• Pat Beers Block
• Good Clinical Practice Program
• February 27, 2004

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Clinical Investigators

• As THE point of contact with study subjects, the
  Investigator is a critical control point
• The success of sponsors, IRBs and FDA in meeting
  their responsibilities depends on the
  investigator meeting his/her responsibilities
• FDAs inspection program for clinical research
  has therefore focused most heavily on inspections
  of clinical investigators

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Definition of Clinical Investigator

• An individual who actually conducts a clinical
  investigation (i.e., under whose direction the
  drug is administered or dispensed to a subject)
• In the event an investigation is conducted by a
  team of individuals, the investigator is the
  responsible leader of the team

--21 CFR 312.3
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Definition of Clinical Investigator

• The definition is important because the clinical
  investigator assumes responsibility for the study
  site
• FDA can take administrative or even criminal
  action against a clinical investigator for
  repeated or deliberate violations of FDA
  regulations

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Subinvestigator(s)

• Other members of the team
• Should be directly involved with subjects in the
  study
• It is the investigator (and not the
  subinvestigators) who is held responsible for
  the study site and subject to enforcement action
  for violations of FDA regulations

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The Form FDA 1572

• For any IND study, the Clinical Investigator must
  complete and sign a Form FDA 1572 and provide
  this to the study sponsor
• Name and address of CI
• Name and code number of any protocol(s)
• Name and address of research facility and any
  clinical labs
• Name and address of the responsible IRB
• Names of subinvestigators
• Signed commitment by the investigator

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The 1572 Commitment

• The investigator is committing to follow all FDA
  regulations that relate to investigator
  responsibilities
• FDA assumes that in signing this commitment, the
  clinical investigator is familiar with and freely
  undertakes these regulatory responsibilities

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Medical Device Studies

• Key difference from FDAs drug/biologics
  regulations
• No FORM FDA 1572 for devices
• Instead, FDA device regulations require a signed
  investigators agreement

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Device Investigators Agreement (21 CFR 812.43(c))

• Still requires a signed statement of the
  investigators commitment to
• Abide by the agreement, investigational plan,
  regulations, and IRB/FDA conditions of approval
• Supervise all testing involving human subjects
• Ensure informed consent
• Provide accurate financial disclosure information

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Clinical Investigators Responsibilities -1-

• Personally conduct or supervise investigations
• Assure that all persons assisting in the conduct
  of the studies are informed of their obligations

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What FDA Looks For

• The extent of personal involvement by the
  clinical investigator
• Is there over-delegation ?
• Is there adequate personal training and
  supervision of staff ?
• Is the investigator devoting adequate time ?
• What are the limits
• How many studies? How many subjects?

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Clinical Investigators Responsibilities -2-

• Ensure informed consent (21 CFR
  Part 50) and IRB review, approval, and reporting
  requirements (21 CFR Part 56) are met

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What FDA Looks For

• Informed consent is more than a form -- it is a
  process
• How personally involved is the investigator in
  this process ?

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Clinical Investigators Responsibilities -3-

• Read and understand the information in the
  Investigators Brochure, including the potential
  risks and side effects of the drug
• Note FDA device regulations do not require an
  Investigators Brochure but rather a report of
  prior investigations of the device (in addition
  to a copy of the investigational plan)

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Clinical Investigators Responsibilities -4-

• Conduct studies according to the relevant,
  current protocol
• Make changes in a protocol only after notifying
  the sponsor and the IRB
• Except where necessary to eliminate apparent,
  immediate hazards to the human subjects

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Clinical Investigators Responsibilities -5-

• Maintain adequate and accurate records
• Records of the disposition of the drug including
  dates, quantity and use by subjects
• Case histories
• Case histories and supporting data

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What FDA Looks For

• Does the Investigator understand and apply the
  basic elements of data quality ?
• Attributable
• Legible
• Contemporaneous
• Original
• Accurate

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What FDA Looks For

• Can the investigator produce source data to
  corroborate the case report form ?
• FDA considers source data to be the first
  commitment of data to durable medium
• Generally where data are FIRST recorded

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Clinical Investigators Responsibilities -6-

• Retention of Study Records
• For 2 years following date marketing application
  is approved for the drug for the indication it
  was investigated
• If no application is to be submitted or if the
  application is not approved for an indication
  until two years after the investigation is
  discontinued and FDA is notified

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Clinical Investigators Responsibilities -7-

• Maintain control of the investigational product
• Administered under his/her personal supervision
  or under the supervision of a subinvestigator
  responsible to him/her

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What FDA Looks For

• Is the drug secure and properly stored ? Does
  drug handling preserve blinding of the study ?
• Is drug administered only under the
  investigators personal supervision or under
  supervision of a subinvestigator responsible to
  the investigator ?

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Clinical Investigators Responsibilities -8-

• Promptly report adverse effects to the sponsor
• Any adverse event that may be reasonably regarded
  as caused by, or probably caused by the drug
• Ensure that any alarming adverse effects are
  immediately reported
• Serious and unexpected adverse events

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Clinical Investigators Responsibilities -9-

• Promptly report to the IRB all unanticipated risk
  to human subjects or others
• This language derives from the Common Rule
  (applicable across U.S. federal agencies
  including and beyond FDA)
• For FDA-regulated research, unanticipated risk
  is most often interpreted as serious and
  unexpected AEs

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Clinical Investigators Responsibilities -10-

• Timeframes for CI reporting are even more
  explicit in FDA device regulations
• Submit to the sponsor and IRB a report of any
  unanticipated device effect ASAP, but no later
  than 10 working days after CI learns of effect
  (21 CFR 812.150(a)(1))

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What FDA Looks For

• Are adverse events appropriately, accurately, and
  promptly identified, recorded and reported ?
• Is there immediate reporting of serious and
  unexpected AEs to facilitate sponsor reporting
  requirements ?
• Are CIs submitting reports to both sponsors and
  IRBs as required ?

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Clinical Investigators Responsibilities -11-

• Required Reports to the Sponsor
• Progress Reports (to facilitate sponsor annual
  reporting requirements to FDA)
• Safety Reports (as above)
• Final Report
• An adequate report shortly after completion of
  the investigators participation
• Financial Disclosure Reports

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Financial Disclosure

• FDA regulations require that an applicant for a
  marketing application to FDA submit financial
  certification or disclosure information on each
  investigator or subinvestigator (including
  spouse/ dependent children) who is directly
  involved in the treatment or evaluation of
  subjects in covered studies
• FDA investigator regulations require that the
  sponsor be provided with sufficient accurate
  information to meet this requirement

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Clinical Investigators Responsibilities -12-

• Make records available for FDA inspection (to
  copy and verify)
• Not required to divulge subject names unless
  records require more detailed study or unless
  there is reason to believe records do not
  represent actual case studies or results
• Agree to comply with all other requirements in
  FDA regulations

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Sponsor-Investigators

• FDA regulations allow an individual to be both
  study sponsor and clinical investigator
• This may include individuals who are studying an
  unapproved drug for academic purposes and not for
  commercial development of the drug
• For example, Physiology studies

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Sponsor-Investigators

• Sponsor-Investigators must comply with BOTH
  sponsor and clinical investigator regulations
• FDA is currently reviewing its approach to
  sponsor-investigators due to recent problems
  (including deaths of subjects) in two
  sponsor-investigator studies

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Who Can Be a Clinical Investigator

• Sponsors are responsible for choosing clinical
  investigators based on their having appropriate
  qualifications, training, and experience
• Usually a medical doctor, although dentists or
  other medical professionals may serve as clinical
  investigators if they are appropriately qualified
  to personally conduct or supervise the protocol

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Who Can Be a Clinical Investigator

• There is no U.S. government sponsored
  certification or training program for clinical
  investigators
• However, there are private training and
  certification programs for investigators in the
  U.S.
• The FDA does not endorse any particular program

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How Does FDA Identify Clinical Investigators

• FDA maintains a publicly available list of all
  clinical investigators who have been involved in
  a study under a U.S. IND
• Bioresearch Monitoring Information System (BMIS)
  File
• Accessible at www.fda.gov/oc/gcp under Related
  Web Sites
• Includes all U.S. investigators as well as
  non-U.S. investigators who have been part of an
  IND study or submitted a 1572

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How Does FDA Identify Clinical Investigators

• BMIS List
• Different from FDAs list of inspected
  investigators and different from FDAs list of
  disqualified or restricted investigators
• Being on this list does NOT imply anything about
  the clinical investigators qualifications or
  performance

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Challenges for FDA

• The list of clinical investigators continues to
  grow
• There are always new clinical investigators
• Many will participate in only a single trial
• The number of non-U.S. investigators on the list
  has grown 16-fold between 1991 and 1999
• Protocols are becoming more complex
• Education and training are the key to quality

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How to Reach Us

• Good Clinical Practice Programs
• 5600 Fishers Lane, Rm. 9C24
• Rockville, MD 20857
• 301-827-3340
• www.fda.gov/oc/gcp
• Gcpquestions_at_oc.fda.gov