Clinical Research at UVa

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Clinical Research at UVa

• Lori Elder
• SOM Clinical Trials Office

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Clinical Trials Office

• http//www/healthsystem.virginia.edu/internet/hes/
  cto/cto_intro.cfm
• Investigator assistance (menu of services)
• SOPs
• IND assistance
• Post-approval monitoring

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Research vs. Practice

• Belmont Report (1979) defined the differences
  between practice and research
• ...practice refers to interventions that are
  designed solely to enhance the well-being of an
  individual patient or client and that have a
  reasonable expectation of success. The purpose
  of medical or behavioral practice is to provide
  diagnosis, preventive treatment, or therapy to
  particular individuals.

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Research vs. Practice

• research designates an activity designed to
  test a hypothesis, permit conclusions to be
  drawn, and thereby to develop or contribute to
  generalizable knowledge

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Applicable regulations

• 45 CFR Part 46
• 21 CFR Parts 11, 50, 54, 56, 312
• International Conference on Harmonization
• HIC
• Clinical research SOPs (SOM CTO website)
• UVa
• State of Virginia

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Investigator responsibilities

• HIC Investigator agreement
• Form FDA 1572

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What is an IND?

• Investigational New Drug application (IND)
• An application to the FDA for permission to ship
  investigational product to investigators for use
  in a clinical study
• Governed by 21 CFR Part 312

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When is an IND required?

• An IND is required to be submitted to the FDA if
  a clinical study will be conducted with a drug /
  biologic that is not yet on the market
• Testing in humans cannot begin until the IND
  application is filed with the FDA.

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IND Types

• Commercial IND
• The IND is the first step to the package insert
  of a drug
• Non-commercial IND
• Investigator IND
• Emergency IND
• Treatment IND

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Sponsor-Investigator

• an individual who both initiates and conducts
  an investigation, and under whose immediate
  direction an investigational drug / biologic is
  administered or dispensed.
• Must abide by those regulations applicable to
  both sponsors and investigators.

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Does your study require an IND?

• Does your study propose the use of a drug /
  biologic not yet on the market?
• Does your study propose the use of a drug /
  biologic that is on the market but approved for a
  different indication?
• Does your study propose to change the route of
  administration or increase the dose of an
  already-marketed drug / biologic?

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IND Exemptions

• CFR 312.2
• The clinical investigation of a drug product
  that is lawfully marketed in the United States is
  exempt from the requirements of this part if all
  of the following apply

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IND Exemptions

• (i) The investigation is not intended to be
  reported to the FDA as a well-controlled study in
  support of a new indication for use nor intended
  to be used to support any significant change in
  the labeling for the drug

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IND Exemptions

• (ii) The drug that is undergoing investigation is
  lawfully marketed as a prescription drug product,
  the investigation is not intended to support a
  significant change in the advertising for the
  product

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IND Exemptions

• (iii) The investigation does not involve a route
  of administration or dosage level or use in a
  patient population or other factor that
  significantly increases the risks (or decreases
  the acceptability of the risks) associated with
  the use of the drug product

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IND Exemptions

• (iv) The investigation is conducted in compliance
  with the requirements for institutional review
  set forth in part 56 and with the requirements
  for informed consent set forth in part 50

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IND Exemptions

• (v) The investigation is conducted in compliance
  with the requirements of CFR 312.7, i.e., the
  investigational drug may not be represented as
  safe or effective for the purposes for which it
  is under investigation, nor may it be
  commercially distributed or test marketed, nor
  may it be sold.

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IND application

• Form FDA 1571 (cover sheet)
• Introductory statement / general plan
• Investigator Brochure (available safety /
  efficacy data)
• Protocol
• Target population (detailed inclusion / exclusion
  criteria)
• Treatment groups (include exact dosing
  information, duration of treatment, etc.)

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IND application

• Proposed endpoints
• Data safety monitoring plan
• Proposed monitoring
• Chemistry, manufacturing and control information
• Form FDA 1572 (statement of investigator)

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SOM CTO Review of IND

• Data safety monitoring plan
• Adverse event reporting
• Safety monitoring
• Safety data
• Data collection forms (Case Report Forms)
• Data variables must correspond to protocol
• Adverse event data

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IND Review Process at FDA

• Most INDs are passively approved
• Upon receipt of IND, FDA will assign an IND
  number
• in most cases, there may be no formal contact
  during the 30 day review period, provided the
  review division has no issues
• studies cannot be initiated until after this 30
  day review period

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Maintaining an IND

• An IND is a living document
• IND Amendments
• Protocol amendments
• Information amendments
• IND safety reports
• Annual reports

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Protocol amendments

• New protocols
• Protocol changes
• modify Phase I in a manner that significantly
  affects safety of subject
• modify Phase 2 or 3 in a manner that
  significantly affects the safety of a subject,
  the scope of the investigation, or the scientific
  quality of the study
• New investigator

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Information Amendments

• Used to report to the FDA new information that
  would not ordinarily be included in a protocol
  amendment or IND safety report, and information
  whose importance dictates that it must be
  reported before the next IND annual report.
• Submitted as necessary, but preferably not more
  frequently than every 30 days.

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IND Safety Reports

• Sponsors must submit IND safety reports to inform
  the FDA of any adverse event (AE) that is
  associated with the use of an investigational
  product and that is both serious and unexpected
• No later than 15 calendar days after initial
  receipt of information

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IND Safety Reports

• Sponsors must submit IND safety reports to inform
  the FDA of details of any unexpected fatal or
  life-threatening event associated with the use of
  the investigational product
• No later than 7 calendar days after initial
  receipt of information

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Annual Reports

• Within 60 days of the anniversary date of the
  IND, the following must be submitted to the FDA.
• Title of study, purpose, patient population,
  status of study (enrollment ongoing, enrollment
  completed-patients in follow-up, analysis, etc.)
• of subjects originally planned, entered to
  date, entered since last annual report (each
  tabulated by age group, gender and race), who
  completed protocol, withdrawn for any reason

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Annual Reports

• Summary information
• narrative or tabular summary of most frequent and
  most serious adverse events organized by body
  system
• summary of all IND safety reports submitted in
  the past year
• listing of all deaths in the study (including
  cause of death)
• listing of all subjects who dropped out of the
  study (including reason for withdrawal)

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What is an Adverse Event?

• any untoward or undesirable sign, symptom or
  medical condition (including abnormal laboratory
  finding)...
• even if the event is not considered to be
  related to the investigation..

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Are these Adverse Events?

• An abnormal white count that is discovered on the
  last day of the study
• Hypertension that worsens during a study
• Heartburn that was present at the start of the
  study and persists throughout the study
• A headache that occurs while an inpatient in a
  study on the GCRC
• Nausea and vomiting that occurs during the study
  but is not felt to be related to the study
  treatment

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What is a Serious Adverse Event?

• Any adverse event that
• results in death
• is life-threatening
• requires inpatient hospitalization (or
  prolonation of hospitalization
• results in a persistent or significant disability
  / incapacity
• results in a congenital anomaly / birth defect
• Is deemed serious based on medical judgement

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Are these Serious Adverse Events?

• Vomiting twice within one hour of ingestion of
  the study drug
• A stroke resulting in slurred speech that
  occurred while under treatment with a study drug
• Death attributed to infection while enrolled in a
  study
• Birth of a deformed infant to a study subject
  seven months after discontinuation of a study

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Serious vs. Severe Adverse Events

• Serious
• A regulatory definition
• Severe
• Severity is a measure of intensity (mild,
  moderate and severe)
• An adverse event can be serious but not severe
• An adverse event can be severe but not serious

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Recording Adverse Events

• Adverse events must be recorded as detailed in
  the data safety monitoring plan of the protocol

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Reporting Adverse Events

• Any serious and unexpected adverse event
• If AE occurred in a subject enrolled in a
  protocol in which UVa is the site that enrolled
  the subject submit the event to the HIC within
  7 calendar days
• If the AE occurred in a subject enrolled in a
  protocol at a site other than UVa submit to the
  HIC within 15 calendar days

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Reporting Adverse Events

• Federal regulatory requirements
• Expedited reporting requirements
• General reporting requirements
• Sponsor requirements
• Data safety monitoring plan

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Documenting Informed Consent

• Use the current version approved by the HIC with
  a non-expired approval stamp
• The subject and the person conducting the consent
  discussion should sign and personally date the
  consent form before any procedures are performed
• Provide the subject with a signed copy of the
  consent

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Documenting Informed Consent

• Retain a signed copy of the consent form for at
  least six years after the study is conducted
  (HIPAA requirement)
• Document in the source document that consent was
  obtained date and sign the note

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Questions?

• Lori Elder
• SOM Clinical Trials Office
• contact 924-8570