Investigational New Drug (IND)
Applications and NMDP Update
Lisa Phillips Johnson, NMDP
ISCT Meeting
May 24, 2010
Objectives…
• Review IND Background and Basics
• Provide Overview of IND Responsibilities and
Content
• Review CBB IND Guidance
• Provide Overview of NMDP Current and Future
IND
• Challenges and Next Steps
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Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
2
What is October 20, 2011?
• ANSWER
• The date FDA requires that all cord blood units
distributed in USA (as interstate commerce or
imported into USA) will need to be distributed
under either…
• an approved biological license application (BLA) as a
licensed biological drug product
OR
• an IND as an unlicensed biological drug product.
• IND is no longer voluntary for CB after this date
per Federal Register announcement 10/20/09
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Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
3
What is an IND?
• In everyday language…
• Investigational New Drug (IND) is when an
experiment is being conducted (a clinical
investigation or protocol) in which a drug (CBU) is
administered/used, involving one or more human
subjects
• Used to collect data to demonstrate safety and
effectiveness of a new drug for a specific use or
treatment in preparation for FDA licensure
• Used to collect safety and efficacy data to support an
additional labeling claim for an already licensed drug
• when drug is used in different way (dose)
• for a different population (kids)
• for a new treatment indication
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What is an IND?
• An IND may include one or multiple studies/research protocols
(umbrella)
• If more than 1 study is under IND, the commonalities are strongly
linked
• FDA approves IND/ protocols (experimental plan) before you start
the investigation
• Holding an IND means
• Responsibility for complying with the requirements of GMPs and
GTPs…..FDA rules for tissues and drugs
• Also complying with FDA requirements for human research (main
sections: 21 CFR Parts 50 and 56)
• includes IRB (human research ethics board) submissions, approvals
and monitoring
• Complying with FDA requirements for INDs (21 CFR 312)
• IND maintenance, updates and oversight, including reporting &
communication with investigators involved in the research and with
the FDA about INDs + clinical trials.gov submission
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FDA defined roles for an IND
Sponsor = The person (can be an establishment) who
takes responsibility for the investigation. The sponsor does
not need to conduct the study, but they are responsible for
the performance and compliance with all aspects of the
CFR related to IND and human research and reporting
functions.
Investigator = The individual who actually conducts the
investigation (with delegates)
Sponsor/ Investigator = An individual who initiates and
conducts the study and has both roles
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Responsibilities of each role…
21 CFR 312
• Sponsor
•
•
•
•
•
•
•
•
Oversight: informed consent, study done per protocol & monitor IND
Investigators are qualified licensed physicians + updated info to FDA
IND Amendments: sponsor submits info to FDA relative to IND
IND safety reports
Annual cost recovery
Annual reports on status and research plan updates
Informing investigators during study (updates/ risks/ benefits)
Adequate records of disposition of drug & record retention for drug
• Investigator
•
•
•
•
Follow the protocol
Timely reporting of adverse events to sponsor
Informed consent and appropriate IRB review requirements met
Accurate, traceable, complete case histories, drug disposition records
and retention
• Sponsor-Investigator
• All of the above
• FDA
• Review, approve and monitor
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What is FDA looking for in an IND?
• Depends on where the drug is in the development
cycle but in general…
• Assure safety and rights of human subject
• Research plan or protocol supports data collection and
evaluation to show safety and effectiveness of drug
• for eventual marketing ….licensure
• IND submission has a standard format
• Guidance for FDA Reviewers and Sponsors: Content
and Review of Chemistry, Manufacturing and Control
(CMC) Information for Human Somatic Cell Therapy
Investigational New Drug Applications (INDs)
• April, 2008
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Overview of an IND
…we always include a cover letter, too
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Under the IND….
…each protocol has standard format
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Is there anything else to highlight?
….Yes, of course!
• Labeling / advertising of an Investigational New
Drug can’t falsely represent the drug as safe and
effective as treatment if not a labeled indication…
• “Caution: New Drug- Limited by Federal law to
investigational use”
• No false or misleading claims in materials,
websites, presentations, promotions, etc.
• No “Viagra-like” TV advertisements
• “Just the facts, ma’am”…
• share scientific data from objective, reliable sources
• Last but not least
• Charging….$$$
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Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
11
Cost Recovery…What is it?
• FDA regulation 21 CFR 312.7 and 312.8
define how you can promote and charge
for a drug under an IND…
• Basic premise is…no profit off an
“unproven” drug under investigation
before it is FDA-approved for that use
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Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
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More about cost recovery …
• Requirements under IND
• Sponsor can’t charge $ without written approval from
FDA
• Submit financial data for re-approval annually to FDA
• Only some expenses allowed as part of “cost recovery”
• Cannot charge price different than approved by FDA to
recover cost of research, development, manufacturing
and handling costs, etc.
• CFR changed in October, 2009
• Direct vs. indirect costs defined specific to cost recovery
calculations
• Added requirement for independent CPA to review and
approve cost recovery calculations as part of annual
submission
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13
Cord Blood IND Specifically…
…See the draft Guidance
• FDA provided us with a draft CB IND Plan
• Draft Guidance for Industry and FDA Staff
• Investigational New Drug Applications (INDs) for Minimally
Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood
Intended for Hematopoietic Reconstitution for Specific Indications
• Defines the minimum requirements for CB
• 21 CFR 312 regulations define IND content
• Draft Guidance outlines minimal approach
• Applies to unrelated cord blood units only (not auto/related)
• Defines who can file an IND
•
•
•
•
•
Cord blood bank (manufacturer)
Registry
Cord blood recipient physician
TC physician
Other
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When is a CBB IND required?
• Products will not meet the criteria for licensure
• Donor eligibility determination (donor screening
and/or testing)
OR
• Can’t demonstrate the “manufacturing criteria”, as
required by licensure guidance, has been met for
inventory (or parts of it)
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FDA Intent…
• It is not FDA intent to limit the units available for
US patients to only licensed units
• Draft IND guidance describes how this transition can
occur so that both licensed and unlicensed units are
available source for transplantation
• Use of unlicensed product--“when such HPC-Cs are not
licensed….and when a suitable HLA matched cord blood
transplant is needed for treatment of a patient….and
there is no satisfactory alternative treatment.”
• Medical decision for what is best for patient
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Draft IND Guidance for CB
Indications for Use
• Hematological malignancies
• Lysosomal storage and peroxisomal
enzyme deficiency disorders
• Hurler Syndrome
• Krabbe Disease
• X-linked Adrenoleukodystrophy
• Primary immunodeficiency diseases
• Bone marrow failure
• Beta thalassemia
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17
What about the other indications?
• Not specifically addressed in this draft guidance
• Based on the requirement for CBUs to be under a
BLA or IND by 10/20/2011…
• Follow what has been outlined earlier for basic IND
processes and human research for unlicensed
products
• Apply concept of off-label use for licensed products
• To support future labeling claim…do under an IND
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What about International CBBs?
• Per the draft guidance
• Non-US HPC-Cs that do not meet the US defined GMP
and GTP regulations and licensing requirements or if
CBB choose not to apply for licensure
• Eligibility (screen/test) per non-US requirements
• GMP/GTP equivalency can’t be met
• IND will be required to support importation of needed
product into USA
• NMDP: 25% of CBUs coordinated are imported from
non-US in FY 2008-2009
• Not expected most international CBBs will submit BLA
• Occasional export to USA
• Challenges to meet licensing/eligibility rules…
• CBB inventory, vCJD risk, “FDA” IDM testing
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Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
19
What about “old inventory” in US CBBs?
• Per the draft guidance
• US HPC-Cs pre-license inventory that cannot be shown
to be equivalent to the licensed inventory per FDAapproved BLA (comparability) for that facility
• Not meet eligibility requirements per today’s world
• GMP/GTP equivalency can’t be met per BLA
• Includes inventory prior to or after 05/25/05
• Different industry approaches over time, process control and
documentation sophistication over the years
• IND will likely be required for older units from many
of our partners to support availability to our patients
• Dependent on our manufacturing process control and
documentation and how FDA views that data and
implements “retrospective comparability”
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Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
20
Will all units need to be licensed in the future?
• Per the draft guidance
• US HPC-C post-license inventory that cannot be shown to be
equivalent to the licensed inventory per approved BLA for the
facility (prospectively)
• FDA recognizes need to bank some units with special circumstances;
to support broader inventory for under-represented populations
(increased HLA diversity)
• Not meet eligibility requirements (positive test for Hepatitis B core
antibody)
• GMP/GTP equivalency can’t be met (potency criteria)
• Per draft guidance, FDA expects this to be limited practice
• IND will be required to support availability to our patients
• A Perspective: Even today, after years of licensure, justified use of
“unlicensed units” still occurs in context of blood components for
transfusion to treat a sick patient
• Don’t get “stuck” on this wording…
• See “uncommon practice” wording as aligning our goals to make the best
product available for our patients as industry continues to improve our
processes and inventory diversity
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
21
What goes in the CBB IND?
• Detailed in draft guidance, with reference to 21
CFR 312 sections for international, pre-licensure
and prospective inventory settings:
•
•
•
•
•
•
Container and supplemental labeling per CFR
Manufacturing (before & after 05/25/05)
Promotion (advertising) and cost recovery ($)
Details of IND format & submission per CFR 312s
Protocol content… Investigator Brochure (if needed)
Outline of Chemistry, Manufacturing & Controls
• Donor eligibility
• Defined release criteria
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Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
22
NMDP IND Plans…
• Current NMDP IND- in place since 1999
• Protocol= A Centralized Cord Blood Registry to
Facilitate Allogeneic, Unrelated Donor Umbilical
Cord Blood Transplantation
• Voluntary IND
• no requirement to establish one
• For US banks and transplant centers only
• Supported data submission to docket as
referenced in licensure guidance for CBU
licensure
• Plus other study objectives
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Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
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Current NMDP CB IND
• Donor population
• Unrelated infant cord blood units donated by healthy
volunteer mothers
• Patient population
• Primary or secondary transplants
• Malignant, non-malignant, metabolic, other indications
• On-going enrollment, no maximum enrollment
• Sponsor
•
NMDP (Dr John Miller as rep)
• Investigators
• USA CBB medical directors
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Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
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Planned NMDP CB IND Protocol
• NMDP is planning a new protocol to enable
distribution of unlicensed units from domestic
and international partners
• Draft guidance INDs for Minimally Manipulated,
Unrelated Allogeneic…
• Non-U.S. HPC-C establishments: existing & future
inventory
• U.S. HPC-C establishments: pre-licensure inventory
• U.S. HPC-C establishments: prospective manufacture of
unlicensed HPC-C
• Expect to address indications beyond those stated in
draft IND guidance for unlicensed units, similar to
previous protocol
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Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
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Planned New IND Protocol
•
•
•
•
Sponsor: NMDP
Principal Investigators: U.S. transplant physicians
Investigative sites: U.S. transplant centers
Study participants: CBBs
• domestic or international
• Test article manufacturer: CBBs
• Test article: unlicensed cord blood units
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Transplant center responsibilities
•
•
•
•
•
•
Designate principal investigator
Submit protocol to their IRB
Obtain research consent from CBU recipients
Continue to report outcomes data to CIBMTR
Report adverse events to NMDP
Collaborate in investigation & follow-up of events
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Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
27
U.S. Cord Blood Bank Responsibilities
•
•
•
•
CBBs must be registered with FDA
Accredited by AABB or NetCord-FACT
NMDP member or participating bank
Follow NMDP standards, complete annual renewal
survey
• Report any FDA enforcement action to NMDP
• Report adverse events to NMDP
• Collaborate in investigation and follow-up of events
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
28
International Cord Blood Bank
Responsibilities
• CBBs must be registered with FDA
• Qualification process by NMDP
• Prefer accreditation by AABB or NetCord-FACT
• Alternatives may include other national accreditation
• Report adverse events to NMDP
• Collaborate in investigation and follow-up of events
• Must comply with NMDP procedures for establishing
donor eligibility, etc.
• Maternal donors are not research subjects
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
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Challenges to Discuss/ Clarify…
…included in the IND
• Domestic Setting
• Container labeling/
representative draft
labeling for historical
inventory
• Drug description and
manufacture process,
pre & post 2005; if
details needed
• Transferred inventory
• Cost recovery specifics
• International Setting
• Container label for
historical and future
• English translation
requirements/details
• CBB vs. Registry
• Drug description and
manufacture process,
pre & post 2005; if
details needed
• Cost recovery specifics
• Level of oversight could
be prohibitive if on-sight
inspections, audits
required
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
30
Another Resource…
• Guidance for Industry IND Meetings for Human
Drugs and Biologics
• Describes how to set-up various meetings with FDA
to discuss an IND
...Questions?
…Thank You!
[email protected]
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Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
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NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
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