Transcript Sponsor-Investigator Responsibilities under an IND Definitions

Sponsor Investigator
Responsibilities under an
IND
Tracy Hysong, MS, CCRP
CTSC Clinical Trials Resource Group
Agenda
 Definitions
 What is an IND and why do I need
one?
 Sponsor-Investigator Responsibilities
under an IND
Definitions
 Investigator means an individual who
actually conducts a clinical investigation
(i.e., under whose immediate 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 (b)
Definitions
 Sponsor means an individual who takes
responsibility for and initiates a clinical
investigation. The sponsor may be an
individual or pharmaceutical company,
governmental agency, academic
institution, private organization, or other
organization. The sponsor does not
actually conduct the investigation unless
the sponsor is a sponsor-investigator
21 CFR 312.3 (b)
Definitions
 Sponsor-Investigator means an individual
who both initiates and conducts an
investigation, and under whose immediate
direction the investigational drug is
administered or dispensed.
– Does not include any person other than an
individual.
– The requirements applicable to a sponsorinvestigator under this part include both those
applicable to an investigator and sponsor.
21 CFR 312.3 (b)
Quiz
 Dr. Smith wrote the protocol,
submitted the IND, and is the only PI
conducting the study. The drug was
supplied by a private pharmaceutical
company. Dr. Smith is a
A) Investigator
B) Sponsor
C) Sponsor-Investigator
Quiz
 Dr. Smith is conducting a study for
Miracle Pharmaceuticals. They hold
the IND and provide the study drug.
Dr. Smith provided advice in
developing the protocol. Dr. Smith is
a(n):
A)Investigator
B)Sponsor
C)Sponsor-investigator
Regulatory vs. Financial
Sponsor
 Regulatory Sponsor
the agency, organization,
company or person primarily responsible for initiating and
overseeing the research and ensuring the study complies
with federal regulations
– For clinical trials (studies involving drugs or biologics) this is
typically the IND holder, for device studies, this is the IDE holder
– For industry-sponsored trials, typically the pharmaceutical/
device/biotechnology company is the regulatory sponsor
– For non-industry sponsored trials, the regulatory sponsor is
typically the PI
 Financial Sponsor
the agency, organization, company,
or person that pays for the trial
Quiz
 Miracle Pharmaceuticals is supplying
the drug and holds the IND. A private
foundation is paying for the study.
Dr. Smith wrote the protocol for
Miracle Pharmaceuticals and the
company submitted it to the IND. Dr.
Smith is conducting the study at his
institution.
Who is the regulatory sponsor?
Who is the financial sponsor?
Who is Dr. Smith?
UCDHS 2012 Full IRB
Committee Review
Of the 66 UC
Davis PI led, 9
(14%) were
clinical trials. 8
of the 9 were
done under
IND (1 was
granted an
exemption)
IND Research at UC Davis
 A Pilot Clinical Trial of the Feasibility and Safety
of Intravitreal Autologous Adult Bone Marrow
Stem Cells in Treating Eyes with Vision Loss from
Retinopathy
 A Double-Blind, Placebo-Controlled, Randomized
Clinical Trial of Allopregnanolone for the
Treatment of Traumatic Brain Injury (allo not
approved for anything)
 Randomized Trial of L-arginine in Severe Asthma
Patients Grouped by Exhaled Nitric Oxide Levels
(L-arginine is a supplement)
Agenda
 Definitions
 What is an IND and why do I need
one?
 Sponsor-Investigator Responsibilities
under an IND
What is an IND?
 An IND is a request for FDA
authorization to administer an
investigational new drug to humans
– Such authorization must be secured prior to
interstate shipment and administration of any
unapproved drug
What is an investigational
drug?
– Investigational drug (aka Investigational New
Drug): drug or biological drug that is used in
a clinical investigation.
– Clinical Investigation: any experiment in
which a drug is administered or dispensed to,
or used involving, one or more human subjects
(an experiment is any use of a drug except for
the use of a marketed drug in the course of
medical practice).
What is the purpose of an
IND?
 It 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 be
performed in accordance with Good Clinical
Practice (GCP)
 Provides an additional level of protection through
FDA oversight
– FDA’s review focuses on safety of human subjects and
ensuring that the studies will produce useful information
to assess safety and efficacy of the test product
Different types of INDs:
 Treatment IND (21 CRF 312.320)
– Investigational New Drugs are used to make
promising new drugs available to desperately
ill patients as early in the drug development
process as possible
– FDA will permit an investigational drug to be
used under a treatment IND if there is:
• preliminary evidence of drug efficacy,
• drug is intended to treat a serious or life-threatening
disease, or
• there is no comparable alternative drug or therapy
available to treat that stage of the disease in the
intended patient population
Different types of INDs:
 Expanded Access: Single patient INDs
– sometimes called "compassionate use"
– use of an investigational drug outside of a
clinical trial to treat a patient with a serious or
immediately life-threatening disease or
condition who has no comparable or
satisfactory alternative treatment options
Content & Format of an IND
– Cover Sheet (Form FDA 1571)
– Table of Contents
– Introductory Statement and General
Investigational Plan
– Investigator’s Brochure
– Clinical Protocol
– Chemistry, Manufacturing and Control (CMC)
– Pharmacology and Toxicology Information
– Previous Human Experience
– Clinical Trials Certification of Compliance (Form
FDA 3674)
– Additional Information
Introductory Statement and
General Investigational Plan
(21 CFR 312.23(a)(3))
 Information about the drug
 Brief summary of previous human
experience
 If the drug has been withdrawn from
investigation or marketing in any country
 Brief description of the overall plan for
investigating the drug product for the
following year
Investigator’s Brochure
(21 CFR 312.23(a)(5))
 If required under 312.55, a copy of the
investigator's brochure
ICH-GCP E6
http://ichgcp.net/7-investigator’s-brochure
Clinical Protocol
(21 CFR 312.23(a)(6))
 Looking for a good template?
http://www.ucdmc.ucdavis.edu/clinicaltrials/
StudyTools/StudyTools.html
CMC
(21 CFR 312.23(a)(7))
 Section describing the composition,
manufacture, and control of the drug
substance and the drug product
– Regulations are specific based on what phase
of the investigation you are at (i.e., the
requirements for a Phase I study are much
different than the requirements for a Phase III
study)
Pharmacology and toxicology
data
(21 CFR 312.23(a)(8))
 Adequate information about
pharmacological and toxicological studies
of the drug involving laboratory animals or
in vitro, on the basis of which the sponsor
has concluded that it is reasonably safe to
conduct the proposed clinical
investigations
Previous Human Experience
(21 CFR 312.23(a)(9))
 For a Phase I study could be none
Additional Information
(21 CFR 312.23(a)(10))
(i)Drug dependence and abuse potential
(ii)Radioactive drugs
(iii)Pediatric studies
Clinical Trials Certification of
Compliance
(Form FDA 3674)=clinicaltrials.gov
Agenda
 Definitions
 What is an IND and why do I need
one?
 Sponsor-Investigator Responsibilities
under an IND
Reminder
 An IND is a request for FDA
authorization to administer an
investigational new drug to humans
Sponsor Responsibilities
Maintain an effective IND
 Select qualified investigators and
monitors
 Ensure ongoing monitoring of
investigations
 Informing Investigators
Partners Human Research Quality Improvement Program
www.partners.org/phsqi
FDA Regulations
CFR 312
1.0 SPONSOR RESPONSIBILITIES (312.50)
1.1 Maintain an effective IND/IDE:
 Protocol amendments (312.30)
o New protocol
o Changes to existing protocol
o New Investigator
 Information Amendments (312.31)
o Essential information not within the
scope of a protocol amendment (e.g.
new technical information,
discontinuation of clinical
investigation)
 IND/IDE safety reports (312.32)
o Serious, related, unexpected or
significant findings to FDA, and all
participating investigators if
applicable, within 15 calendar days)
o Fatal or life-threatening reports
(telephone or fax within 7 calendar
days)
o Follow-up information to a safety
report (submitted as soon as
available)
 Annual reports (312.33)
o Within 60 days of the anniversary
date that the IND/IDE went into
effect
Corresponding Onsite Documents
All correspondence with FDA including:
Original IND/IDE application
(including 1571)
FDA letter of no objection, if provided
Amendments (w/ 1571)
IND/IDE Safety reports (w/ 1571)
Evidence of correspondence to
other investigators [multi-site]
Annual reports (w/ 1571)
Other correspondence with FDA (e.g.
response to clinical hold, general
correspondence)
Sponsor Responsibilities
 Maintain an effective IND
Select qualified investigators
and monitors
 Ensure ongoing monitoring of
investigations
 Informing Investigators
Partners Human Research Quality Improvement Program
www.partners.org/phsqi
1.2 Select qualified investigators and
monitors (312.53, 312.57(b))
 Select PIs qualified by training and
experience
 Ship investigational product only to those
investigators participating in the trial
 Accurate records of financial disclosure
according to 21 CFR 54
 Select monitors qualified by training and
experience
Signed FDA form 1572 /Investigator
Agreement
Investigator CV and licensure
__________________
FDA form __ __ __ ___
Monitor of study:
PI
Other:
_____________________________
1.2 Select qualified investigators and
monitors (312.53, 312.57(b))
 Select PIs qualified by training and
experience
Signed FDA form 1572 /Investigator
Agreement
Investigator CV and licensure
 Ship investigational product only to those
investigators participating in the trial
IRB approval
 Accurate records of financial disclosure
according to 21 CFR 54
FDA form 3455 for PI and sub –
investigators listed on 1572
 Select monitors qualified by training and
experience
Monitor of study:
PI
Other:
_____________________________
CV and training experience of monitor
Ensure monitor is trained on protocol
Sponsor Responsibilities
 Maintain an effective IND
 Select qualified investigators and
monitors
Ensure ongoing monitoring of
investigations
 Informing Investigators
Partners Human Research Quality Improvement Program
www.partners.org/phsqi
1.3 Ensure ongoing monitoring
investigations (312.56)
 Ensure proper monitoring
 Ensure PI compliance or discontinue
shipments of the investigational
drug/device
 Review and evaluate drug/device safety
and effectiveness
Correspondence with monitor
Documentation of monitoring
(monitoring log)
Documentation of safety monitoring
plan
Co-monitoring/QA visits
Trip Monitoring Reports
Who will be reviewing safety data:
PI
DSMB
Medical Monitor
Other
____________
Reports/meeting minutes from DSMB
and/or Medical monitor
Documentation of data monitoring
plan
Research team has been trained on data
collection sheets and/or CRFs
 Discontinue investigation within 5
working days when unreasonable and
significant risk to subject are identified
Notify all investigators, IRB, and FDA
if investigation is discontinued
 Ensure IRB & FDA approval to resume a
terminated study
IRB approval prior to resuming a
terminated study
Sponsor Responsibilities
 Maintain an effective IND
 Select qualified investigators and
monitors
 Ensure ongoing monitoring of
investigations
Informing Investigators
Partners Human Research Quality Improvement Program
www.partners.org/phsqi
1.4 Informing Investigators (312.55)
 Provide all clinical investigators with
Investor’s Brochure (IB)
Current Investigator’s Brochure
For Multi-center study
Documentation that all sites have
received IB
 Inform investigators of new observations
discovered by or reported to the sponsor
on the investigational product
Documentation of communication with
investigators regarding new observations
and adverse events.
Investigator Responsibilities
 Assure IRB review and approval
 Maintain adequate and accurate case
histories on each subject’s participation in
the trial
 Conduct study according to signed
investigator statement, protocol, and
applicable regulations
 Personally conduct and supervise the
investigation
 Protect the rights, safety, and welfare of
study subjects
 The Investigator is responsible for providing
Sponsor with reports
Assure IRB review and
approval
 What documentation could we file to
indicate that we received IRB review
and approval?
2.1 Assure IRB review and
approval (312.66)
IRB documentation:
Initial review
Continuing review
Amendments
Adverse event reports
Unanticipated events
Protocol deviations
Current IB
Other IRB correspondence
Investigator Responsibilities
 Assure IRB review and approval
 Maintain adequate and accurate case
histories on each subject’s participation in
the trial
 Conduct study according to signed
investigator statement, protocol, and
applicable regulations
 Personally conduct and supervise the
investigation
 Protect the rights, safety, and welfare of
study subjects
 The Investigator is responsible for providing
Sponsor with reports
Maintain adequate and
accurate case histories on
each subject’s participation in
the trial
 What documentation can we provide
to indicate that we are maintaining
adequate and accurate case histories?
Informed consent for all subjects
2.2 Maintain adequate and accurate
Documentation that informed
case histories on each subject’s
participation in the trial (312.62 (b)) consent was obtained prior to study
procedures
Documentation that subject was
given a copy of signed and dated
consent form
Subject eligibility documented
Source data
Progress notes
CRFs
Concomitant medications
recorded
Signature/date of staff obtaining
data
Investigator Responsibilities
 Assure IRB review and approval
 Maintain adequate and accurate case
histories on each subject’s participation in
the trial
 Conduct study according to signed
investigator statement, protocol, and
applicable regulations
 Personally conduct and supervise the
investigation
 Protect the rights, safety, and welfare of
study subjects
 The Investigator is responsible for providing
Sponsor with reports
Conduct study according to
signed investigator statement,
protocol, and applicable
regulations
 What documentation can we provide
that we are conducting the study
according to the 1572, the protocol,
applicable regulations?
Report violations/deviations to
2.3 Conduct study according to
IRB
signed investigator statement,
protocol, and applicable regulations Promptly report to IRB any “on(312.60)
site” adverse events/unanticipated
adverse device effects in
accordance with institutional
requirements
Obtain informed consent in
accordance with provisions in 21
CFR 50
Investigator Responsibilities
 Assure IRB review and approval
 Maintain adequate and accurate case
histories on each subject’s participation in
the trial
 Conduct study according to signed
investigator statement, protocol, and
applicable regulations
 Personally conduct and supervise the
investigation
 Protect the rights, safety, and welfare of
study subjects
 The Investigator is responsible for providing
Sponsor with reports
Personally conduct and
supervise the investigation
 What documentation can PI provide
to prove he/she is personally
conducting and supervising the trial?
2.4 Personally conduct and
supervise the investigation (312.60)
Ensure:
 Appropriate delegation
 Adequate training
 Adequate supervision
Delegation log
Staff training log
Routine research team meeting to
review trial progress, AEs,
protocol changes
Meeting minutes
Routine meetings with study
monitor
Procedures for internal review of
data
Investigator Responsibilities
 Assure IRB review and approval
 Maintain adequate and accurate case
histories on each subject’s participation in
the trial
 Conduct study according to signed
investigator statement, protocol, and
applicable regulations
 Personally conduct and supervise the
investigation
 Protect the rights, safety, and welfare of
study subjects
 The Investigator is responsible for providing
Sponsor with reports
Protect the rights, safety, and
welfare of study subjects
 What documentation can we provide
that the Investigator is protecting the
rights, safety, and welfare of the
subjects?
2.5 Protect the rights, safety, and
welfare of study subjects (312.60)
Adhere to protocol
Provide reasonable medical care
for AEs
Inform subject when medical care
is needed for conditions unrelated
to research
Investigator is available to
subjects during conduct of study
Appropriate delegation to Co –
Investigator if PI is not available
Investigator Responsibilities
 Assure IRB review and approval
 Maintain adequate and accurate case
histories on each subject’s participation in
the trial
 Conduct study according to signed
investigator statement, protocol, and
applicable regulations
 Personally conduct and supervise the
investigation
 Protect the rights, safety, and welfare of
study subjects
 The Investigator is responsible for providing
Sponsor with reports
Drug Accountability
 The Sponsor is responsible for record
of drug disposition
 The Investigator is required to maintain
adequate records of the disposition of the
drug
 The Investigator is responsible to ensure
control of investigational drug
Drug Receipt
3.1 The Sponsor is responsible for
record of drug disposition (312.57,
Drug received from Industry
312.59)
Drug accountability log includes:
 Maintain adequate record of receipt
Receipt date
and shipment of investigational
Quantity
drug/device
Lot #
 Assure return of all unused
Return/disposition
investigational drug/device from
Method of disposal
individual investigators participating
in trial or authorize alternative
Drug manufactured onsite
disposition of unused product
 Maintain written records of any
Drug Shipment
disposition of the drug/device
Single center study – no drug
shipment
Drug/device accountability log
includes:
Date
Quantity
Lot #
Return/disposition
Method of disposal
Drug Accountability
 The Sponsor is responsible for record of
drug disposition
 The Investigator is required to
maintain adequate records of the
disposition of the drug
 The Investigator is responsible to ensure
control of investigational drug
3.2 The Investigator is required to
maintain adequate records of the
disposition of the drug/device
(312.62)
Drug/device dispensing record
including:
Research Pharmacy will manage
drug
Date
Lot #
Quantity
ID of subject
administered/implanted
Disposition/record of return
ID of person dispensing
Return of drug, count & reason
Drug Accountability
 The Sponsor is responsible for record of
drug disposition
 The Investigator is required to maintain
adequate records of the disposition of the
drug
 The Investigator is responsible to
ensure control of investigational drug
Enrollment log/ Randomization
3.3 The Investigator is responsible
to ensure control of investigational log
drug (312.61)
Delegation of Responsibility log
 Drug will be administered only to
those subjects enrolled in the clinical
study and under investigator or
designee’s supervision
Record Retention and FDA
Inspection
4.0 RECORD RETENTION (312.57(C), 312.62(C))
4.1 Sponsor and Investigator: Retain
Records are on file
records for 2 years after marketing or 2
years after investigational use is
discontinued and FDA is notified
5.0 FDA INSPECTION (312.58, 312.68)
5.1 Sponsor and Investigator: Inspection Upon request, permit FDA officer to
of Investigators records and reports
access, copy and verify any records or
reports made by the investigator
Top 10 Bioresearch monitoring Observations Used in Turbo EIR
(2011-Mar2012)
An investigation was not conducted in accordance with the
[signed statement of investigator] [investigational plan]
Failure to prepare or maintain [adequate] [accurate] case
histories with respect to [observations and data pertinent to the
investigation] [informed consent].
Drug disposition
Informed
consent
http://swog.org/Visitors/spring12Gp
Mtg/Lanham.pdf
When is an IND necessary?
 http://www.ucdmc.ucdavis.edu/clini
caltrials/IND/ind_documents/7842df
t.pdf
Guidance for Industry Investigational New
Drug Applications (INDs)— Determining
Whether Human Research Studies Can Be
Conducted Without an IND
IND exemptions
 The clinical investigation of a drug
product that is lawfully marketed in
the United States is exempt from the
requirements of an IND if ALL of the
following apply:
#1 There is no intent to report the investigation to FDA as
a well-controlled study in support of a new indication
and no intent to use it to support any other significant
change in the labeling of the drug
#2 In the case of a prescription drug, the investigation is
not intended to support a significant change in the
advertising for the drug
#3 The investigation does not involve a route of
administration, dose, patient population, or other
factor that significantly increases the risk (or decreases
the acceptability of the risk) associated with the use of
the drug product (21 CFR 312.2(b)(1)(iii))
#4 The investigation is conducted in compliance with the
requirements for review by an IRB (21 CFR part 56)
and with the requirements for informed consent (21
CFR part 50)
#5 The investigation is conducted in compliance with the
requirements of § 312.7 (i.e., the investigation is not
intended to promote or commercialize the drug
product)
#3 The investigation does not involve a route of
administration, dose, patient population, or other
factor that significantly increases the risk (or
decreases the acceptability of the risk) associated
with the use of the drug product (21 CFR
312.2(b)(1)(iii))
 Route of Administration
– For example, there could be a significant
increase in risk if a marketed drug for oral
administration is converted to a dosage form
that is to be administered by IV
 Dose
– Increases in dose, frequency, or duration of
administration, compared to labeled dosing
regimens, can significantly increase the risk in
a study using a marketed drug
#3 (cont’d) The investigation does not involve a route
of administration, dose, patient population, or other
factor that significantly increases the risk (or
decreases the acceptability of the risk) associated
with the use of the drug product (21 CFR
312.2(b)(1)(iii))
 Patient population
– The acceptability of known and unknown risks
can vary considerably across different
treatment populations (see § 312.2(b)(1)(iii))
• For example, a drug with significant toxicity can be
approved for use in a population with life-threatening
or severely debilitating disease because the risk of
toxicity is acceptable in that population
Does the sponsor intend to (1) report the investigation
to FDA as a well-controlled study in support of a new
indication, (2) use it to support any other significant
change in the labeling of the drug, or (3) use it to
support a significant change in the advertising (for
prescription drugs only) for the drug?
– Whether a planned clinical investigation will be
used to support a new indication, other
significant labeling change, or advertising
claim may not always be known or apparent at
the outset of the investigation
What if I’m still not sure if I
need an IND?
– Contact CTSC Clinical Trials Resource Group
and request a consultation
– CTSC can help you prepare a request for
exemption
• Content
• Timelines
– CTSC can help you prepare an IND
• Content
• Timelines
http://www.ucdmc.ucdavis.edu/clinicaltrials
/Forinvestigators/forinvestigators.html
Quiz
 Dr. Zang wants to conduct a clinical
trial using Zapper (an oral tablet
approved for curing the common cold
in adults) to treat adults with
attention deficit disorder. Does she
need an IND?
 Why or why not?
Quiz
 Dr. Zang wants to conduct a clinical
trial using Zapper (an oral tablet
approved for curing the common cold
in adults) to treat adults with the
common cold. She would like to use
2x the approved dose. Does she need
an IND?
 Why or why not?
Side note: Oncology
IND Exemptions for Studies of Lawfully Marketed
Drug or Biological Products for the Treatment of
Cancer (the cancer treatment guidance)
http://www.fda.gov/downloads/Drugs/Guidances
/UCM071717.pdf
This guidance is intended to assist sponsors in
deciding whether a study of marketed drugs or
biological products for treating cancer falls within
the exemption under § 312.2(b)(1) (21
CFR312.2(b)(1)) from the general requirement
to submit an investigational new drug
application(IND).