Transcript Title goes here - University of Washington

FDA Approvals, IND, IDE and
Clinical Trials
March 16, 2011
Gerberding Hall 142, University of Washington
Faculty Brown Bag Series on Research
Speakers
Lynn Rose, Research Associate Professor,
Pediatrics; Director, Regulatory and Clinical
Affairs, Seattle Children’s Research Institute
Ann Melvin MD, MPH, Associate Professor
Pediatrics – Infectious Diseases
Seattle Children’s Hospital
Co-director Regulatory Support and Bioethics
Core - ITHS
Faculty Brown Bag Series on Research
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Learning Goals of Presentation
1. Brief history behind FDA regulations and processes
2. Review IND and IDE Exemptions
3. Practical Considerations for Writing for INDs and
IDEs
4. Review Investigator Commitments and Common
Deficiencies
5. Overview of resources available through ITHS
Confidential
Faculty Brown Bag Series on Research
Safety is the Key to Initiating
Clinical Trials
• Long, sad history of both abuses and ignorance
leading to clinical disasters:
– From past disasters come current laws
– As the years have passed, more and more regulations (i.e.
disasters) have been passed
– People more risk averse
Confidential
Faculty Brown Bag Series on Research
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Confidential
Faculty Brown Bag Series on Research
1937: Sulfanilamide Elixir
• S.E. Massengill developed Sulfanilamide
Elixir for pediatric indications
– Sulfa drug dissolved in diethylene glycol
• First death reported in October 1937
– Eventually 107 people died, mostly children
– 108th death was the chemist who invented it (suicide)
– Dr. Geiling at the U. Chicago showed the solvent was
toxic
• FDA seizures and prosecution
– “Misbranded” – “elixir” implied it contained alcohol,
which it didn’t
– Massengill Co. paid a fine of $26,100
Confidential
Faculty Brown Bag Series on Research
Federal Food, Drug,
and Cosmetic Act of 1938
• Increased emphasis on safety:
– Manufacturer had to test any new drug for safety and
report results to the FDA
• No standards for safety testing were established
• No requirements for efficacy
– Authorized FDA to conduct factory inspections
• No manufacturing standards were set
– Labeling had to include
• All ingredients and quantity of each
• Directions for use, Warnings about dangers
– Product was considered misbranded if it was dangerous to health
when used in the dosage recommended in the label.
• No oversight of clinical trials was mandated
Confidential
Faculty Brown Bag Series on Research
Thalidomide
• “Wonder drug” for insomnia,
coughs, colds, and headaches. Also
an effective antiemetic for morning
sickness.
• Thalidomide distributed to >1000
U.S. doctors on an “investigational”
basis
– > 20,000 patients received the
drug; 624 were pregnant
– Doctors were “invited” to report
on their results, but were under
no obligation to do so
• NDA for thalidomide was assigned to
a new FDA examiner, Dr. Frances
Kelsey, who had studied in the lab of
Dr. Geiling as a graduate student
Faculty Brown Bag Series on Research
Thalidomide Aftermath
• Dr. Kelsey won the
President’s Medal for
Distinguished Federal
Civilian Service from
President John F. Kennedy
(highest recognition
possible for civil service)
Confidential
• Drug reform proposals that
had been languishing were
resurrected and enacted
without a single dissenting
vote in either the House or
Senate
Faculty Brown Bag Series on Research
Kefauver-Harris Amendments of 1962
• FDA gained jurisdiction over testing of drugs before they
would be approved for marketing
– Drug firms (“sponsors”) had to apply to the FDA to perform human
trials of a new drug: Investigational New Drug application, or IND
– Sponsors had to inform FDA of what happened during clinical testing
• Patients in trials had to give informed consent (WWII
aftermath)
• Animal testing had to be conducted prior to human testing
• Experiments had to be properly planned, and include controls
• Investigators conducting trials had to be qualified
– Sponsors had to describe the scientific training and experience
necessary to test the safety of the drug
• Drug had to show efficacy before it could be marketed
• Established Good Manufacturing Practices
Confidential
Faculty Brown Bag Series on Research
Following the Dalkon Shield Deaths:
Medical Device Amendments of 1976
•
Law passed to ensure safety and effectiveness of medical devices, including
diagnostics
•
Required manufacturers to register with FDA and follow standard quality control
procedures
•
Identified 3 classes of medical devices, each with unique requirements for
marketing authorization
– Class I – lowest risk devices and lowest set of requirements
• Clinical testing not required for marketing approval
• No regulatory application (i.e. 510 (k) or PMA required for marketing authorization)
– Class II –medium risk devices, higher performance standards required
• Marketing authorization requires 510 (k) application
• Clinical testing may be required if product has no “predicate” as comparator
– Class III – highest risk devices, highest level of performance standards
• Investigational Device Exemption (IDE)
• Premarket Authorization (PMA) for Marketing Approval
Confidential
Faculty Brown Bag Series on Research
Examples of Medical Device Classifications
Medical Device Classes:
Additional Classification:
Class I
“De Novo”
Class II
Device "types" that have
never been marketed in the
U.S., but whose safety
profile and technology are
now reasonably well
understood
General Controls
Most exempt from
premarket submission
Special Controls
Premarket Notification
[510(k)]
Class III
Premarket
Approval
Require Premarket Application [PMA]
Faculty Brown Bag Series on Research
Humanitarian Device
Exemption (HDE)
Devices for orphan diseases
Intended to benefit patients in
diagnosis and/or treatment of disease
or condition affecting or manifested in
fewer than 4,000 patients per year in
the United States
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Since 1976…
 The regulations embodied in the Food and Drug Administration
Modernization Act (1997) have continued to evolve as new problems
emerge
 Requirements for post-market surveillance protocols
 Safety data continues to be prioritized by FDA (over efficacy) when
reviewing IND applications because history shows that safety risks lurk
in unusual places
 Cell lines (e.g., viral, mycoplasm contamination)
 Expression Systems (e.g. antibiotic selection)
 Formulation (e.g., sulfanilamide)
 Contaminants from manufacturing
 Guidance Documents have proliferated to aid investigators
in understanding the requirements for INDs and IDEs
 Product and Indication Specific
Confidential
Faculty Brown Bag Series on Research
Understanding the Regulations for INDs and IDEs
• Review 21 CFR Part 312- Investigational New Drug Application
• Review 21 CFR Part 812 – Investigational Device Exemptions
– Table of Contents Clearly Delineated
• Review FDA Guidance Documents related to product type,
disease, animal models, etc.
• Consider a Pre-IND/IDE meeting:
•
•
•
•
Before you embark on animal safety studies
Once preclinical data is sufficient to have a meaningful discussion.
To clarify the product classification and FDA review division
To determine if study is eligible for IND or IDE waiver
Confidential
Faculty Brown Bag Series on Research
Investigational New Drug (IND) Applications
• IND applications are required for clinical studies of
investigational drugs that are not “exempt” from the
IND regulations
• Investigational drugs means a “new” drug or
biological drug that is used in a clinical investigation.
• The term “new” encompasses both unapproved
drugs and approved drugs that are used in new ways
(i.e., new indications)
Confidential
Faculty Brown Bag Series on Research
Conditions for IND Exemption
• Conditions for IND Waivers are provided in 21 CFR Part 312.2
– Study results will not be reported to FDA for the purpose of
changing the label or adding a new indication (Industry
Sponsor)
– Study results will not be used to change the advertising of
the drug (Industry Sponsor)
– The investigation does not involve a route of administration
or dosage level or use in a patient population or other factor
that significantly increases the risks (or decreases the
acceptability of risks) associated with use of the drug product
(Industry and Academic Sponsors)
– The investigation is conducted in compliance with
requirements for institutional review
– The study will not be used for off-label promotion of the drug
(Industry Sponsor)
Confidential
Faculty Brown Bag Series on Research
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Practical Considerations for IND Waivers
― Would a change in the route of administration alter the safety profile?
 Target Organ may change (i.e. inhaled vs parenteral)
 Pharmacokinetics may be altered (i.e. increased renal exposure)
― Are the approved doses appropriate for the new indication?
 Do animal model data suggest that higher doses should be tested?
― Is the intended patient population is within the same age range studied in
approved indication
•
Safety risks in young or older populations may be unknown
― Does the intended patient population have a disease condition that would
put it at different (i.e., unknown) and/or greater risk than the population
studied for the approval (i.e., pediatric versus adult, healthy versus sick)
•
•
What were the safety findings for the original indication?
Are those findings relevant for the condition under study?
― Don’t short-change the study to avoid an IND
― Read the label!
Confidential
Faculty Brown Bag Series on Research
Investigational Device Exemption
(IDE) Waivers
• Requirement for IDE based primarily on Device
Class (i.e. I, II, or III)
– Class III highest risk category
– Existence of a “predicate” device
• IDE Waivers Based on Risk of Device and
Experience with Device Type
– Significant Risk (Requires an IDE to initiate a study)
– Nonsignificant Risk (May require an IDE)
– Exempt (Does not require an IDE)
Faculty Brown Bag Series on Research
IDE Exempt Studies
• 510(k)-cleared and HDE- or PMA-approved
devices, if used in accordance with approved
label;
• Consumer preference testing of marketed
device;
• Combinations of legally marketed devices;
• Custom devices (NARROWLY defined);
• Foreign Studies; Declaration of Helsinki
• Studies of diagnostic devices (with some
caveats)
Faculty Brown Bag Series on Research
Significant Risk Device
• Is intended as an implant and presents a
potential for serious risk to the health, safety,
or welfare of a subject;
• Is purported or represented to be for use
supporting or sustaining human life and
presents a potential for ….;
• If for use of substantial importance in
diagnosing, curing, mitigating, or treating
disease, or otherwise preventing impairment of
human health and presents a ….;
• Otherwise presents a potential for …..
• Is typically designated as a Class III device
Faculty Brown Bag Series on Research
Nonsignificant Risk Devices
• An NSR Device is one that does not meet the
definition of a Serious Risk Device
• Are typically Class I or Class II devices
Faculty Brown Bag Series on Research
Who decides whether a device study is
SR or NSR?
• Study Sponsors make initial determination and
present case to IRB
• Unless FDA has already determined risk level, it
is the responsibility of the IRB to make the
determination
• FDA is available to consult with sponsor or IRB
• In cases of disagreement, FDA trumps IRB
Faculty Brown Bag Series on Research
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Some Practical Considerations
 Plan ahead, evaluate the IND or IDE requirements well before you
want to write one
 Don’t avoid the FDA – you can save so much time if you ask the
questions you need to ask
 Read the drug labels, they guide you in determining the information
you need to obtain about your own compound
 Be thorough in your literature search, the FDA certainly will be
 Plan sufficient time to complete the IND or IDE – it can take months to
assemble and review all of the data, not days!
 Understand import restrictions on clinical supplies and foreign devices
 Proofread, proofread, proofread
 Poor grammar, sloppy formatting, lack of consistency can impact your working
relationship with the FDA
 Ask for help – no sense wasting time on rework
Confidential
Faculty Brown Bag Series on Research
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Common IND Misconceptions
 The mechanism of action must be well understood prior to
submitting an IND for a new drug or biologic drug
 Important, but don’t shortchange safety
 Use animal models to collect safety information
 No safety findings is Good!
 Yes, BUT you need to understand the margin of safety between the proposed
human dose and the toxic dose
 FDA will ask you to find the toxic dose
 Regulatory requirements are not relevant to academic research
 Early choices can make or break successful translation to industry



Cell line lineage, passage number, viral testing procedures
Antibiotic selection techniques – use of ampicillin not acceptable
Assay reproducibility and accuracy
 Regulatory science is not “research”
 FDA requirements are science-based
 Your grant application is a clinical protocol
Confidential
Faculty Brown Bag Series on Research
IND/IDE Applications are not Forms
• They represent a
major scientific effort
• Require commitment
of time and effort!
• They carry a
commitment to follow
the regulations
Confidential
Faculty Brown Bag Series on Research
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FDA Form 1572 or Investigator Agreement*
 Legal Contract between Investigator and Sponsor and FDA
 Provides the sponsor with information about the
investigator’s qualifications and others at the clinical site
 Informs the investigator of his/her obligations and provides
the investigator’s written commitment to follow pertinent
FDA regulations.
 Making a willfully false statement is a criminal offense
under 18 U.S.C. 1001.
 Submission of a deliberately false statement to the sponsor
or to the agency can be taken into consideration in a
disqualification proceeding.
*for devices
Confidential
Faculty Brown Bag Series on Research
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Statement of Investigator (paraphrased)
 Agrees to follow the investigational plan (i.e., the protocol)
 Agrees to personally conduct or supervise the conduct of the
investigational study and to ensure that all associates, colleagues,
understand their obligations to the study

Agrees to inform any study subjects that the drugs /devices are
being used for investigational purposes and obtain their consent for
participation in the study
 Agrees to report adverse experiences that occur in the course of
the investigation

Agrees to maintain adequate and accurate records and to make
those records available for inspection

Agree to obtain and document IRB approval for the study
 Adequately monitor supplies of investigational products used in the
Confidential study
Faculty Brown Bag Series on Research
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Clinical Investigator Inspections
 You can expect to be inspected by the FDA if:
 You are participating in a Phase 3 industrysponsored study that will support registration (i.e.,
approval) of a new drug or biological drug
 You are participating in an industry study that will
support registration of a new medical device or
diagnostic
 You are conducting a study funded by the FDA
 You are conducting high risk research
 A complaint has been lodged against you
 You have never been inspected before
Confidential
Faculty Brown Bag Series on Research
Clinical Investigator Inspection Search
Type
Classification
Deficiency Codes
DA
VAI
05
DA
VAI
03,06
DA
VAI2
01
FC
VAI
05,18
DA
VAI2
03,04,05,06,07
DA
VAI2
03,04,05,06
Bockow, Barry I MD Arthritis NW
DA
VAI
05,18
Bowden, Raleigh A
MD
DA
VAI
03,04,05
DA
NAI
00
Name
Location
Aboulafia, David M
MD
Virginia Mason Med
Ctr
Scribner Kidney
Ahmad, Suhail MD
Ctr/Univ
Washington
Altman, Leonard C NW Asthma &
MD
Allergy Ctr
Bensinger, William I Fred Hutchinson Ca
MD
Res Ctr
Bierman, Charles W
a.s.t.h.m.a. inc
MD
Blackmon, John R
Univ Washington
MD
Hosp
Fred Hutchinson Ca
Res Ctr
Virginia Mason Med
Caplan, Robert A MD
Ctr
FC = for cause; DA = data audit
http://www.accessdata.fda.gov/scripts/cder/CLIIL/index.cfm?fuseaction=Search.Search
Faculty Brown Bag Series on Research
FDA Inspection Codes
Classification Codes
• NAI – No Action Indicated
• VAI – Voluntary Action
Indicated
• OAI – Official Action
Indicated
• CANC – Cancelled
• WASH – Washout
Faculty Brown Bag Series on Research
Frequency of Classification
in Washington State
Inspections
•
•
•
•
•
NAI – 27%
VAI – 69.5%
OAI – 1%
CANC – 1.5%
WASH – 0.5%
Errors Frequently Committed by Clinical Investigators
in Washington State
Deficiency Code
(%)
Deficiency Code
(%)
00 - No deficiencies noted
6.3
10 – Inappropriate delegation of
authority
0.9
01 – Records availability
2.6
11 – Inappropriate use of IND
0.6
02 – Failure to obtain/document
informed consent
1.4
12 – Failure to list additional investigators
2.0
03 – Inadequate informed consent form
21
13 – Subjects receiving simultaneous
investigational products
0.6
04 – Inadequate drug accountability
10
14 – Failure to obtain/document IRB
approval
0.9
05 – Failure to follow investigational plan
21
15 – Failure to notify IRB of changes
4.0
06 – Inadequate and inaccurate records
19
16 – Failure to report adverse drug
reaction
5.4
07 – Unapproved concomitant therapy
1.4
17 – Submission of false information
0
08 – Inappropriate payment to subjects
0.6
18 - Other
2.6
09 – Unapproved use of drug (no IND)
0
* Compiled from CDER Clinical Investigator Inspection
Database n=197 Inspections (1989-2009)
Faculty Brown Bag Series on Research
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ITHS Preclinical Research and Development
Core




Consulting on IND/IDE Content
Preparation of IND/IDE
Review Development Programs
Assist in identification of industry and academic
partners
 Funding Program for Translational Research
(Ignition Awards for Nonhuman Primate studies,
Pharmaceutics, and Manufacturing)
 ([email protected])
Faculty Brown Bag Series on Research
Thank you
For additional information contact:
Lynn Rose
206-884-7540
Faculty Brown Bag Series on Research
CLINICAL TRIALS: HOW
DO I GET STARTED?
Faculty Brown Bag Series on Research
Objectives
• Provide an overview of:
– How to assess study feasibility
– Clinical research approval process- UW
– Where you can go for help
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Faculty Brown Bag Series on Research
Study feasibility
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•
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•
•
Population
Procedures
Collaborations
Staff
Budget
Space
etc.
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Faculty Brown Bag Series on Research
Population
• Do you have access to the right patient
population?
• Are the enrollment goals realistic?
• Will you need to recruit outside of your
system?
• Will enrollment compete with other studies?
• Are there special consent issues?
• Have you reviewed the inclusion/exclusion
criteria and are they too restrictive?
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Faculty Brown Bag Series on Research
Procedures
• Are procedures approvable?
• Are procedures
frequent/painful/inconvenient?
• Do procedures require special
equipment/expertise?
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Faculty Brown Bag Series on Research
Collaborations
• Do you need additional specialists?
• Do you need access to outside
clinics/schools/etc?
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Faculty Brown Bag Series on Research
Personnel
•
•
•
•
•
Do you have qualified staff?
Any special training required?
Do you need an RN?
Do you have time to devote to the protocol?
Does your staff have time to devote to the
protocol?
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Faculty Brown Bag Series on Research
Budget Considerations
•
•
•
•
•
•
•
•
•
Your time
Staff time
Sub-investigator time
Consultant time
Cost of procedures
Cost of labs
Cost of space (CRC)
Cost of shipping
Records Storage
• Cost of storing
specimens
• Pharmacy costs
• Cost of data collection
system
• Cost of monitoring
(study and site)
• Cost of statistician
• Manuscript preparation
and presentation
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Faculty Brown Bag Series on Research
Budgets
• If budget is determined by sponsor do they allow
time for
– Study start-up activities (non-refundable)
– Training
– Unanticipated activities – protocol amendments,
unanticipated monitoring visits, audits, etc
– Keep in mind industry budgets are negotiable
• If you are writing the budget, is the RFA amount
sufficient for all the study activities?
– If not – what will need to be cut from the protocol.
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Faculty Brown Bag Series on Research
Budgeting help
• CRBB Detailed Budget Tool
• https://depts.washington.edu/crbb/Submit_B
udget.shtml
• For help contact CRBB
– [email protected]
– 206-543-7774
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Faculty Brown Bag Series on Research
Space
• Do you have room for:
– Research personnel
– Study binders
– Any equipment needed
– Lab supplies OR
• Will you have to look for more space?
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Faculty Brown Bag Series on Research
Start up activities - contracts
• Read the protocol
– Make sure everyone on the research team reads
the protocol
• Decide if the study is feasible
• Let your Division/Departmental administrator
know you are thinking of pursuing/accepting
the contract
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Faculty Brown Bag Series on Research
Considerations if you didn’t write the
protocol
•
•
•
•
Is it well designed?
Any ethical issues?
Is there potential benefit to participants?
Will the sponsor allow modifications if you
don’t think it is feasible as written?
• Are the visits/procedures onerous for
participants?
• Drug available at the end of the study?
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Faculty Brown Bag Series on Research
Study start-up activities - Develop all
study materials
• Regulatory Binder
• Study visit records
• Case report forms
• Eligibility checklist
• Adverse event report forms
• Protocol deviation report forms
• Screening logs
• Training logs
• PI Delegation log
ITHS forms - www.iths.org/forms
https://www.washington.edu/research/clinical-research-handbook//
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Faculty Brown Bag Series on Research
Study start up activities – training
•
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•
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Human Subjects Protection
Good Clinical Practice
HIPAA
Clinical Research Budget and Billing
Office of Sponsored Research seminars
Clinical Research Education Series – ITHS
Fundamentals of Clinical Research - ITHS
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Faculty Brown Bag Series on Research
Who to go to for help
• General questions about clinical research at the UW
– Ella Mae Kurashige, Director Clinical Research
Services - [email protected]
• Office of Sponsored Programs http://www.washington.edu/research/osp/?page=o
sp
• ITHS Research Navigator - https://www.iths.org/help
• UW Clinical trials handbook
https://www.washington.edu/research/clinicalresearch-handbook//: submission checklists, repository
for how to do clinical research at the UW Medicine
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Faculty Brown Bag Series on Research
Who to go to for help
• How to get assistance from a research coordinator –
Michelle Doyle – ITHS Research Coordinator Core
[email protected]
• Study design and biostatistical help – ITHS Center for
Biomedical Statistics
http://depts.washington.edu/medstat/Welcome.html
• Investigational Drug Service – Sheree Miller –
[email protected]
• Research Bioethics – Ben Wilfond - ITHS RSB core
[email protected]
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Faculty Brown Bag Series on Research
Who to go to for help
• Research labs - Research Testing Service –
[email protected]
• Regulatory questions – Ann Melvin, Jason Malone ITHS
RSB core [email protected]
• Working with the UW CRC – Paul Hughes –
[email protected]
• ITHS Bionutrition Core – Holly Callahan - [email protected]
• ITHS Body Composition and Exercise Laboratory– Holly
Callahan - [email protected]
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Additional Resources
• Institute for Translational Health Sciences (ITHS) www.iths.org
• Additional education http://www.iths.org/education
• Translational Research Toolkit – UW Healthlinks: search for
Translational Research Toolkit
http://healthlinks.washington.edu.offcampus.lib.washington.edu/
• PRIMER toolkit - http://researchtoolkit.org/
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