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Title: The Difference Between Practice and Research What the FDA Expects You to Understand


1
The Difference Between Practice and Research
What the FDA Expects You to Understand
  • Harvey M. Arbit, PharmD, MBA, RAC, CCRP
  • University of Minnesota
  • Director, IND/IDE Assistance Program,
  • Academic Health Center
  • Adjunct Associate Professor,
  • College of Pharmacy
  • Phone 612-625-0930
  • Fax 612-625-3956
  • E-mail arbit002_at_umn.edu
  • www.ahc.umn.edu/research/ind-ide/

2
Outline
  • Practice vs Research
  • Sponsor and Investigator
  • Good Clinical Practice
  • Clinical Trial Monitoring
  • Data Safety Monitoring Board
  • Q A

3
Practice vs Research
4
Clinical Practice ? Clinical Research
  • Special training is required.
  • Clinical research must be conducted according to
    the written protocol with a full understanding of
    the risk to the subjects.
  • The laws, regulations and guidelines for clinical
    research are detailed and specific.

5
Clinical Investigation(Drug Research)
  • Clinical investigation - any experiment that
    involves a test article and one or more human
    subjects. 21 CFR 50.3(c)
  • Clinical investigation any experiment in which
    a drug is administered or dispensed to, or used
    involving, one or more human subjects. For the
    purposes of this part, an experiment is any use
    of a drug except for the use of a marketed drug
    in the course of medical practice. 21 CFR
    312.3(b)
  • Practice - exercise of an occupation or a
    profession
  • No protocol
  • Administer to all patients
  • Some documentation
  • Not intended to publish
  • Billable to insurance
  • Research systematic investigation designed to
    contribute to generalizable knowledge
  • Protocol
  • Administer to some patients
  • Much documentation
  • Intend to publish
  • Not billable to insurance

6
Clinical Trials vs Medical Practice
  • Clinical trails are not to evaluate a medicine
    under actual medical practice conditions, but
    rather under selected and often artificial
    conditions to answer best the trials objectives.
  • Controlled clinical trials cannot by definition
    mimic actual medical practice conditions.
  • Bert Spilker, Guide to Clinical Trials, 1996,
    p.554

7
Practice of Medicine
  • The practice of medicine combines both science as
    the evidence base and art in the application of
    this medical knowledge in combination with
    intuition and clinical judgment to determine the
    treatment plan for each patient. (ref. Wikipedia,
    2007)

8
"Off-Label" Use of Marketed Drugs, Biologics and
Medical Devices
  • Good medical practice and the best interests of
    the patient require that physicians use legally
    available drugs, biologics and devices according
    to their best knowledge and judgment.
  • If physicians use a product for an indication not
    in the approved labeling, they have the
    responsibility to be well informed about the
    product, to base its use on firm scientific
    rationale and on sound medical evidence, and to
    maintain records of the product's use and
    effects.
  • Use of a marketed product in this manner when the
    intent is the "practice of medicine" does not
    require the submission of an Investigational New
    Drug Application (IND), Investigational Device
    Exemption (IDE) or review by an Institutional
    Review Board (IRB).
  • However, the institution at which the product
    will be used may, under its own authority,
    require IRB review or other institutional
    oversight.
  • (FDA Information Sheet Guidance for IRB, CI and
    S. 1998)

9
Clinical Trial
  • A comparison test of a medication or other
    medical treatment, versus a placebo, other
    medications/devices, or the standard medical
    treatment for a patient's condition.
  • Researchers test hypotheses and observe what
    happens, clinical trials can be seen as the
    application of the scientific method to
    understanding human biology.
  • Clinical trials are closely supervised by
    appropriate regulatory authorities. All studies
    that involve a medical or therapeutic
    intervention on patients must be approved by an
    ethics committee before permission is granted to
    run the trial. (ref Wikipedia, 2007)

10
Investigational Use of Marketed Drugs, Biologics
and Medical Devices
  • The investigational use of approved, marketed
    products differs from off-label" use.
  • "Investigational use" suggests the use of an
    approved product in the context of a clinical
    study protocol. When the principal intent of the
    investigational use of a test article is to
    develop information about the product's safety or
    efficacy, submission of an IND or IDE may be
    required.
  • The clinical investigation of a marketed drug or
    biologic does not require submission of an IND if
    all six of the following conditions are met

11
Investigational Use of Marketed Drugs, Biologics
and Medical Devices (cont.)
  • (i) it is not intended to be reported to FDA in
    support of a new indication for use or to support
    any other significant change in the labeling for
    the drug
  • (ii) it is not intended to support a significant
    change in the advertising for the product
  • (iii) it does not involve a route of
    administration or dosage level, use in a subject
    population, or other factor that significantly
    increases the risks (or decreases the
    acceptability of the risks) associated with the
    use of the drug product
  • (iv) it is conducted in compliance with the
    requirements for IRB review and informed consent
  • (v) it is conducted in compliance with the
    requirements concerning the promotion and sale of
    drugs and
  • (vi) it does not intend to invoke exemption from
    informed consent.
  • (FDA Information Sheet Guidance for IRB, CI and
    S. 1998)
  • (IND Exemption Criteria, 21 CFR 312.2(b))

12
IND Assessment Process
  • When determining if the risk is significantly
    increased, the parts of the protocol that are
    examined are those that concern
  • dose,
  • schedule,
  • route of administration, and
  • patient population.

13
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14
Oncology Drugs
  • Guidance for Industry IND Exemptions for
    Studies of Lawfully Marketed Drugs or Biological
    Products for the Treatment of Cancer (Jan. 2004)
  • Focus is on whether risk is significantly altered
  • Discusses a range of potential scenarios and
    factors that may alter risk

15
Sponsor and Investigator
16
http//aapp.org/pdf/HansMayoPresentation.pdf
17
Sponsor21 CFR 312.3(b)
  • An individual or company who takes responsibility
    for and initiates a clinical investigation.
  • The sponsor does not actually conduct the
    investigation unless the sponsor is a
    sponsor-investigator.

18
Sponsor-Investigator 21 CFR 312.3(b)
  • An individual who both initiates and conducts an
    investigation.
  • The term refers only to an individual.
  • Must comply with the requirements of both an
    investigator and a sponsor.

19
Form FDA 1571
  • Investigational New Drug Application

20
When a sponsor signs the 1571 he/she agrees to
the following
  • Wait 30 days before beginning the study
  • Not begin or continue the study if placed on
    clinical hold
  • IRB will be responsible for review and approval
    of the study
  • Conduct the study in accordance with all
    applicable regulatory requirements
  • WARNING A willfully false statement is a
    criminal offense.

21
Responsibilities of Sponsors and Investigators
21 CFR 312 Subpart D
  •    312.50 - General responsibilities of
    sponsors.    312.52 - Transfer of obligations
    to a contract research organization.   
    312.53 - Selecting investigators and monitors.
       312.54 - Emergency research under   
  • 312.55 - Informing investigators.   
    312.56 - Review of ongoing investigations.   
    312.57 - Recordkeeping and record retention.   
    312.58 - Inspection of sponsor's records and
    reports.    312.59 - Disposition of unused
    supply of investigational drug.

22
Investigator 21 CFR 312.3(b)
  • An individual who actually conducts a clinical
    investigation.

23
Form FDA 1572
  • Statement of Investigator

24
When an investigator signs the 1572 he/she
commits to the following
  • To conduct the study according to protocol
  • To personally supervise or conduct the
    investigation
  • To inform the subjects of the investigational
    status of the test article
  • To report adverse events to the sponsor
  • To read and understand the Investigators
    Brochure
  • To inform all support personnel of the
    investigation requirements

25
1572 (Cont.)
  • To maintain adequate records and make them
    available for inspection
  • To assure that the IRB is in compliance
  • To assume responsibility for initial and
    continuing review by the IRB
  • To promptly report study changes and
    unanticipated risks to the IRB
  • Not make any changes in the research without IRB
    approval
  • To comply with the requirements regarding the
    obligations of clinical investigators
  • WARNING A willfully false statement is a
    criminal offense.

26
Responsibilities of Sponsors and Investigators
21 CFR 312 Subpart D
  •    312.60 - General responsibilities of
    investigators.
  •    312.61 - Control of the investigational drug.
  •    312.62 - Investigator recordkeeping and
    record retention.
  •    312.64 - Investigator reports.
  •    312.66 - Assurance of IRB review.
  •    312.68 - Inspection of investigator's records
    and reports.
  •    312.69 - Handling of controlled substances.
  •    312.70 - Disqualification of a clinical
    investigator.

27
Good Clinical Practice (GCP)
28
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29
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30
Protocol elements for IND 21 CFR
312.23(a)(6)(iii)
  • Statement of the objectives
  • Names and qualifications of investigators
  • Inclusion/exclusion criteria and number of
    subjects
  • Design of the study and methods to minimize bias
  • Dose and duration of exposure
  • Observations/measurements to fulfill objectives
  • Clinical procedures to monitor the effects of the
    drug to minimize risk

31
Elements of a Clinical Trial Protocol (GCP
section 6)
  • Background information
  • Trial objectives
  • Trial design
  • Selection and withdrawal of subjects
  • Assessment of efficacy
  • Assessment of safety
  • Statistical plan
  • Access to source documentation, QC/QA, ethics,
    data handling, record keeping, financial/insurance
    , publication

32
Protocol Compliance
  • It doesnt matter who wrote the protocol or
    whether the trial is funded by the DHHS or
    regulated by FDA NO change can be implemented
    without prior IRB approval (except to mitigate
    immediate hazard). The plan submitted to (and
    approved by) the IRB cannot be changed without
    approval. Some changes must also be submitted to
    the FDA.

33
Clinical Trial Monitoring
34
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35
Proper Monitoring(FDA Guideline for the
Monitoring of Clinical Investigations)
  • To assure
  • adequate protection of the rights of human
    subjects and
  • the safety of all subjects involved in clinical
    investigations and
  • the quality and integrity of the resulting data
    submitted to the FDA.

36
Purpose of Monitoring (GCP section 5.18.1)
  • Validity and Accuracy
  • To verify that
  • Rights and well-being of subjects are protected
  • Reported data are accurate, complete, and
    verifiable from source documents
  • Conduct of trial is in compliance with approved
    protocol, GCP, and regulatory requirements

37
Site/Clinical Monitoring
  • Staff internal to the sponsor or a group under
    contract to the sponsor generally perform
    site/clinical monitoring.
  • They perform on site monitoring of individual
    case histories, assess adherence to the protocol,
    ensure the ongoing implementation of appropriate
    data entry and quality control procedures, and in
    general assess adherence to good clinical
    practices.
  • In blinded studies, these monitors remain blinded
    to study arm assignment.

38
Focus of Monitoring Visits
  • Informed consent / HIPAA forms
  • Source documents / CRFs
  • Product accountability
  • Protocol adherence
  • AE / Safety reporting

39
Data Safety Monitoring Board (DSMB)
40
DSMB
  • All clinical trials require safety monitoring but
    not all trials require monitoring by a formal
    committee external to the trial organizers and
    investigators.
  • A DSMB is not needed or advised for every
    clinical study.
  • Several factors are relevant to determining
    whether or not to establish a DSMB for a
    particular trial. These relate primarily to
    safety, practicality, and scientific validity.

41
DSMB Composition
  • Most DSMBs are composed of
  • clinicians with expertise in relevant clinical
    specialties
  • at least one biostatistician knowledgeable about
    statistical methods for clinical trials
  • a medical ethicist knowledgeable about the
    design, conduct, and interpretation of clinical
    trials

42
Data Safety Monitoring GCP 5.5.2
  • The sponsor may consider establishing an
    independent data monitoring committee to assess
    the progress of a clinical trial, including the
    safety data and the critical efficacy endpoints
    at intervals, and to recommend to the sponsor
    whether to continue, modify, or stop a trial.
  • The data monitoring committee should have written
    operating procedures and maintain written records
    of all its meetings.

43
What FDA Looks For
44
What FDA Looks For
  • Does the investigator understand and apply the
    basic element of quality data?
  • Attributable, Legible, Contemporaneous, Original,
    Accurate
  • Can the investigator produce source data to
    corroborate the case report form?
  • Source data Generally where data are first
    recorded
  • Must make records available for FDA inspection
    (to copy and verify)

45
What FDA Looks For (cont.)
  • Is the drug/device secure and properly stored?
  • Does the handling preserve blinding of the
    study?
  • Is the drug/device administered/used only under
    the investigators personal supervision or under
    supervision of a sub-investigator responsible to
    the investigator?

46
Regulatory Actions
  • Form FDA 483
  • Warning Letter
  • Notice of Initiation of Disqualification
    Proceeding and Opportunity to Explain
  • Disqualified/Restricted/Assurances List
  • Administrative Actions List

47
Summary Points of Importance
  • A clinical research career is built on ethics and
    integrity.
  • Ask a lot of questions before determining if
    off-label use is practice or research. It
    depends
  • Clinical monitoring is not an option.
  • Signed forms 1571 and 1572 are contracts with the
    Federal government.
  • The FDA is your partner like it or not.

48
Are there any Questions ? Thank you !
  • IND-IDE Assistance Program (IAP)
  • IAP Director
  • Harvey M. Arbit, PharmD, MBA, RAC, CCRP
  • arbit002_at_umn.edu
  • 612-625-0930
  • IAP website
  • www.ahc.umn.edu/research/ind-ide
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