investigational new drug (ind) applications and nmdp update

Investigational New Drug (IND) Applications and NMDP Update

Lisa Phillips Johnson, NMDPISCT Meeting May 24, 2010

NATIONAL MARROW DONOR PROGRAM®

Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM2

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



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



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



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



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



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



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



Overview of an IND …we always include a cover letter, too



Under the IND….…each protocol has standard format



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….$$$



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



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



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



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)



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



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



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



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



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 FDA-approved 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”



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



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



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



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



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



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



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



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


• Collaborate in investigation and follow-up of events



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


• Collaborate in investigation and follow-up of events

• Must comply with NMDP procedures for establishing donor eligibility, etc.

• Maternal donors are not research subjects



Challenges to Discuss/ Clarify……included in the IND

• 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

• 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



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? [email protected]

…Thank You!

mailto:[email protected]

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