Transcript Clinical Trial Quality and Compliance: An FDA Perspective

THE UNIVERSITY OF NEW MEXICO ▪ HEALTH SCIENCES CENTER
Clinical and Translational Science Center (CTSC)
http://hsc.unm.edu/research/ctsc/
4/2009
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An exemption from the law which
otherwise requires that a drug (biologic,
device) be approved before it can be
transported across state lines
The standard for approval is evidence of
safety and efficacy
The IND exemption is granted for
purposes of clinical investigation
(research)
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Affirms a body of knowledge about the
manufacturing, pharmacology, and
toxicology of the drug to support its use in
human testing
Requires that the clinical investigation(s)
be performed in accordance with Good
Clinical Practice (GCP)
Provides an additional level of protection
through FDA oversight
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Any of:
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Article recognized in the U.S. Pharmacopeia, official
Homeopathic Pharmacopeia of the US, or official
National Formulary, or any supplement
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Article intended for use in the diagnosis, cure,
mitigation, treatment, or prevention of disease in
man or other animals
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Any of:
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Article (other than food) intended to affect the
structure or any function of the body of man or
other animals
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Article intended for use as a component of any
article specified in clauses above
Section 201(g) of the FD&C Act
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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
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In general: An IND is required when
an unapproved drug (or biologic) is
used in a clinical investigation
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No IND is needed when an approved
product is used in the course of medical
practice (even for an indication different
from the approved indication)
But an IND may be required when an
approved products is used in a clinical
investigation
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An IND is needed if:
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The clinical investigation is intended to be
reported to FDA as a well-controlled study
in support of a new indication or a
significant change in the labeling of the
drug
The clinical investigation is intended to
support a significant change in advertising
for the product
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With the above caveats, clinical investigation of
an approved product may be exempt from IND
requirements if:
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The investigation does not involve a route of
administration or dosage level or use in a patient
population or other factor that significantly increases
risks AND
The investigation is conducted in accordance with
IRB and informed consent requirements
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FDA has generally allowed the IRB to
assess whether risk of an approved
product is increased for a given protocol
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But FDA retains final authority for such
determinations
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It is also important to note that shelf
chemicals which bear the same “name”
as an approved product are not
considered as “lawfully marketed”
equivalents of the approved product
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Approval is specific to dose, formulation,
and applicant
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Drugs (CDER)
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Biological Products (CBER)
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(301) 827-0373
Medical Devices (CDRH)
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Drug Information Branch: (301) 827-4573
IDE Staff: (301) 594-1190
Food Safety (CFSAN): (202) 418-3126
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GCP Regulations
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IND/IDE Regulations: 21 CFR Part 312/812
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IRB Regulations: 21 CFR Part 56
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Informed Consent Regs: 21 CFR Part 50
All are accessible at:
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www.fda.gov/oc/gcp
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IND Forms
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Available on-line through:
(ADD LINK)
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General Investigation Plan
Investigator’s Brochure
Protocol(s): Later protocols submitted as
amendments
Chemistry, manufacturing and control
information
Animal pharmacology and toxicology
information
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Previous human experience
Additional information
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Dependence and abuse potential
Plans for pediatric studies
Amount of information required in each
section depends on novelty of the drug, extent
studied, and known or suspected safety
concerns
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IND sponsors are required to obtain a
signed FDA Form “1572” from each clinical
investigator, containing:
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 responsible IRB
 Names of co-investigators
 Signed commitment by the investigator
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Personally conduct or supervise
investigations
Ensure all persons assisting in conduct of
studies are informed of their obligations
Ensure informed consent (21 CFR 50) and
IRB review, approval , and reporting (21
CFR 56) requirements are met
*(Form FDA 1572: #9. Commitments)
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Conduct studies according to relevant,
current protocol
Make changes in a protocol only after
notifying the sponsor
Maintain adequate and accurate records
Make records available for inspection
Agree to comply with all other
requirements in 21 CFR 312
*(Form FDA 1572: #9. Commitments)
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FDA also has responsibilities under GCP
The focus of FDA’s IND Review is on safety for
human research subjects and ensuring that the
studies will produce useful information to
assess safety and efficacy of the test product
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Medical Officer
Consumer Safety Officer/Project Manager
Statistician
Chemist
Pharmacologist
Human Biopharmaceutics
(Microbiologist)
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Review team has 30 days to review
Focus of review is always on safety/
human subject protection
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No News = Good News
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“Clinical Hold”
 Legal order to delay or stop the study in the U.S.
 Subjects may not be given the investigational drug
 May be imposed if:
 Exposure of subjects to unreasonable risk (includes
manufacturing problems)
 Investigator brochure is misleading, erroneous, or
materially incomplete
 Investigator is not qualified
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Review Team Monitors
New Protocols (IND amendments)
 Safety reports
 Annual reports
 Additional chemistry, animal toxicology,
microbiology data
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Review team is available to consult/meet with
sponsors: advise on protocol design, advise on
drug development plan
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Studies performed outside of the U.S. may be
conducted with or without IND
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With an IND:
 Test article can be exported from the U.S.
 Study must conform to U.S. IND
regulations (including U.S. IRB and
informed consent rules)
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Studies performed outside of the U.S. may be
conducted with or without IND
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Without an IND
 May be acceptable for FDA review in
support of a marketing application
 Export of the test article from the U.S. must
conform to FDA regulations
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Mechanisms (21 CFR 312.110)
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FDA authorization of a written request
from the person that seeks to export
 Adequate information; investigational
purposes only; can be legally used in the
importing country for investigation; specifies
quantity/frequency of shipment
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FDA authorization of a formal request
from the government of the receiving
country
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1996 law also allows drug export for
investigational use without prior FDA
approval if intended for use in one of 25
countries
 Australia; Canada; Israel; Japan, New
Zealand; Switzerland; European Union
Member States (15), Iceland, Norway,
and Liechtenstein
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Center for Drugs
ODE I
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Cardio-Renal (110)
 301-594-5300
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Center for Drugs
ODE II
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Neuropharm (120)
 301-594-2850
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Oncology (150)
 301-594-2473
Anesthetic, Critical
Care & Addiction
(170)
 301-827-7410
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Metabolic/Endocrine
(510)
 301-827-6430
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Pulmonary (570)
 301-827-1050
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Center for Drugs
ODE III
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Medical Imaging &
Radiopharm (160)
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Center for Drugs
ODE IV
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 301-827-2120
 301-827-7510
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GI & Coagulation
(180)
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 301-827-7310
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Repro/Urologic (580)
 301-827-4260
Anti-Infective (520)
Antiviral (530)
 301-827-2330
Special Pathogens &
Immunologic (590)
 301-827-2336
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Center for Drugs
ODE V
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Derm/Dental (540)
 301-827-2021
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Anti-Inflammatory,
Analgesic &
Ophthalmic (550)
 301-827-2040
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Over-the-Counter
(OTC) (560)
 301-827-2222
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Center for Biologics (CBER)
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Office of Vaccines Research and Review
 (301) 827-0654
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Office of Blood Research and Review
 (301) 827-3524
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Office of Therapeutics Research and Review
 (301) 827-5099
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OGD Regulatory Support Branch
 (301)
827-5862
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Center for Devices and Radiological Health
(CDRH)
General, Restorative, and Neurological
Devices: (301) 594-1184
 Clinical Laboratory Devices: (301) 5943084
 Cardiovascular and Respiratory
Devices: (301) 443-8320
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Center for Devices and Radiological Health
(CDRH)
Ophthalmic and ENT Devices: (301)
594-2205
 Reproductive, Abdominal, and
Radiological Devices: (301) 594-5072
 Dental, Infection Control, and General
Hospital Devices: (301) 443-8879
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IND sponsors/researchers are required to
report serious non-compliance
But anyone can report complaints in FDAregulated clinical trials to FDA
FDA’s GCP website (www.fda.gov/oc/gcp)
highlights where to report complaints in
clinical trials