Title: The Difference Between Practice and Research What the FDA Expects You to Understand
1The 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/
2Outline
- Practice vs Research
- Sponsor and Investigator
- Good Clinical Practice
- Clinical Trial Monitoring
- Data Safety Monitoring Board
- Q A
3Practice vs Research
4Clinical 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.
5Clinical 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
6Clinical 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
7Practice 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)
9Clinical 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)
10Investigational 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
11Investigational 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))
12IND 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.
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14Oncology 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
15Sponsor and Investigator
16http//aapp.org/pdf/HansMayoPresentation.pdf
17Sponsor21 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.
18Sponsor-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.
19Form FDA 1571
- Investigational New Drug Application
20When 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.
21Responsibilities 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.
22Investigator 21 CFR 312.3(b)
- An individual who actually conducts a clinical
investigation.
23Form FDA 1572
- Statement of Investigator
24When 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
251572 (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.
26Responsibilities 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.
27Good Clinical Practice (GCP)
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29(No Transcript)
30Protocol 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
31Elements 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
32Protocol 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.
33Clinical Trial Monitoring
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35Proper 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.
36Purpose 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
37Site/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.
38Focus of Monitoring Visits
- Informed consent / HIPAA forms
- Source documents / CRFs
- Product accountability
- Protocol adherence
- AE / Safety reporting
39Data Safety Monitoring Board (DSMB)
40DSMB
- 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.
41DSMB 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
42Data 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.
43What FDA Looks For
44What 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)
45What 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?
46Regulatory Actions
- Form FDA 483
- Warning Letter
- Notice of Initiation of Disqualification
Proceeding and Opportunity to Explain - Disqualified/Restricted/Assurances List
- Administrative Actions List
47Summary 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