Who Tells the IRB What to DO?April 4, 2017
P. Pearl O’Rourke, M.D.
Director, Human Research Affairs
What do I feel like requiring today?
IRB Rules of
Engagement
IRB Chair
Why the IRB does what it does
• Federal and state laws
• Case Law
• Condition of Grant Award
• The Boston Globe
Federal and state lawsCase Law
Condition of Grant AwardThe Boston Globe
• Common Rule*
• FDA regulations*
• HIPAA – Privacy Rule*
*never-ending interpretation and guidance
The Common Rule
Subpart A General description; defines research,
subject, IRB processes
Subpart B Fetuses and pregnant women
Subpart C Prisoners
Subpart D Children
Federal laws
• Address IRB structure, membership and process
• Address IRB membership
• Mandate independence of the IRB
IRB Responsibilities
• Initial Review*
– Full or expedited
• Continuing Review
• Approval of Amendments
• Adverse Event Reporting
* This is an ethical AND scientific review
IRB Review
• Scientific and ethical review
• Scientifically invalid research is not ethical
• Research that does not answer the question(s) posed is not ethical
• Research that does not add somethingvaluable to medical science is not ethical
What do the Rules Cover?
• Common Rule: Research supported or conducted by the Federal Government
• FDA Regs: Research regulated under a specific statute
N.B. Human subject research that is neither supported by the Federal Government nor regulated by the FDA is not subject to direct Federal oversight.
Federal laws and the IRB
• Definitions
• Membership
• Operations
Research Definition
• Systematic investigation, including
research development, testing and
evaluation, designed to develop or
contribute to generalizable knowledge.
Is it Research? Or Care?
Clinician? Researcher?
Patient? Subject?
You receive the following anonymous letter:
"Dear Sir, I am writing (anonymously) to inform you of this unauthorized medical study on unknowing human clinic patients. These people had two different doctors and operations (on each side of face) and were never told! The chairman (Aston) conducted the study without institutional approval. We are not guinea pigs. Thank you."
Manhattan Eye, Ear and Throat Hospital: 1992-3
• Research goal:
– To compare “deep” versus “superficial” surgery for face lifts
• Of note, both are accepted procedures
• Methods:
– 21 patients (20F:1M)
– Two teams of surgeons• “Deep” team did surgery on one side of the face
• “Superficial” team did surgery on the other side
Human Subject Definition
• A living individual about whom an
investigator conducting research obtains:
– Data through intervention or interaction
with the individual, or
– Identifiable information.
Human Subject Definition
• A living individual about whom an
investigator conducting research obtains:
– Data through intervention or interaction
with the individual, or
– Identifiable information.
Is it IDENTIFIABLE?
YES NO
Is it IDENTIFIABLE?
YES NO
HIPAA
Common Rule
State Laws
Institutional Policies
So if identifiability is so
important…what elements should
be considered?
• General demographics
• Health information
• Genetic information
Reality
IdentifiablePretty much identifiable‘Sorta’ identifiableCould-be-perhapsNot very identifiablePretty much not identifiableOnly Latanya Sweeney knows
Not identifiable
The Science of Reidentification
• Reliance on ‘auxiliary’ information and data sets
– Examples for persons in the US
87% of the population can be identified using
Zip code + DOB + Sex
53% of the population can be identified using
City + DOB + Sex
18% of the population can be identified using
County + DOB + Sex
Common Rule:How identifiability is defined
• Allows judgment– the identity of the subject is or may readily be
ascertained by the investigator or associated with the
information
Reality and the Common Rule
Human Subjectaka identifiable
Not Human Subjectaka not identifiable
Reality and the Common Rule
Human Subjectaka identifiable
determination by a different IRB
Not Human Subjectaka not identifiable
Enter HIPAA
• Identifiability defined by what is not de-
identified
– Two Safe Harbor Methods
• Stripping of 18 HIPAA identifiers
• “…a person with appropriate knowledge of and
experience with generally accepted statistical and
scientific principles and methods for rendering
information not individually identifiable.”
Identifiability: the 18 identifiers (1)
• Names
• Geographic subdivisions smaller than a State, including street address, city, county, precinct, zip code and their equivalent geocodes, except for the initial 3 digits of the zip code if, according to the current policy available from the Bureau of the Census
– The geographic unit formed by combining all zip codes with the same 3 initial digits contains more than 20,000 people; AND
– The initial 3 digits of the zip code for all geographic units
containing 20,000 or fewer people is changed to 000.
Identifiability: the 18 identifiers (2)
• Dates (except yr) directly related to an individual (e.g., DOB, discharge date, date of death) and all ages over 89 and all elements of dates (including yr) indicative of such age, except that such ages and elements may be aggregated into a single category of age 90 or older
• Telephone numbers
• Fax numbers
• Electronic mail addresses
• Social Security Numbers
• Medical Record Numbers
• Health plan beneficiary numbers
• Account numbers
Identifiability: the 18 identifiers (3)
• Certificate/license numbers
• Vehicle identifiers and serial numbers, including license plate numbers
• Device identifiers and serial numbers
• Web Universal Resource Locators (URLs)
• Internet Protocol (IP) address numbers
• Biometric identifiers, including finger and voice prints
• Full face photographic images and any comparable images; and
• Any other unique identifying number, characteristic or code
Reality and HIPAA
Identifiable
Limited Data Set
De-identified
When is Genetic Data Identifiable?
• Genetics– Unique
– But alone not sufficient to be identifiable
Genetic Information
• Not enough emphasis on the type/amount
of genetic information
• ‘GWAS, SNP – it is all the same to me!”
Genetic Information
Is It Identifiable: Do We Care?
• A link is required
• BUT – even with ‘anonymized’ data:
– Are there enough existing genetic analyses
that would allow a simple merge to find a
specific individual?
Fingerprints
• You find my fingerprints on the murder
weapon…can you identify me?
• Maybe
– NO:
• If I have never had my fingerprints formally taken
– YES:
• If my fingerprints are on file
Local Example
• Anonymous discarded tissue made available to researchers
• One investigator gets 200 samples of adults with asthma on steroids – no other identifiers
– ‘Recognizes’ the genetic pattern from on of the samples and is able to identify the person as someone who had been in a previous study
Reality and Geneticists
‘Genetic data’ should be considered identifiable
‘Genetic data’ is unique – and only theoretically identifiable
So What’s an IRB to do?R
ealit
y
Co
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on
Ru
le
HIP
AA
AN
PR
MG
enet
icis
ts
Oth
er G
enet
icis
ts
Applying identifiability
Research
Clinical Care
IRB action
Informed Consent
Why the Tissue/Data Was Initially Obtained
Research
Clinical Care
IRB action
Informed Consent
Why the Tissue/Data Was Initially Obtained
Secondary Research Uses
Is There Excess Tissue?
YES NO
Is It Identifiable?
IRB action Consent or Waiver
YES NO
Research
Clinical Care
IRB action
Informed Consent
Why the Tissue/Data Was Initially Obtained
Secondary Research Uses
IRB action Consent or Waiver
Is It Identifiable?
YES NO
• Existing* tissue/data, if not identifiable– Not a human subject
– No worry about consent (Common Rule)
– No worry about authorization (HIPAA)
• If identifiable– Voila! A human subject!
– IRB must determine need for informed consent and
possibly authorization (HIPAA)
Therefore…
* Either from clinical care or an earlier research protocol
In Summary…
Why the IRB does what it does
• Federal and state laws
• Case Law
• Condition of Grant Award
• The Boston Globe
Tuskegee
• 1972
Washington Evening Star breaks story of Tuskegee scandal with headline: “Syphilis patients died untreated”
Tuskegee Syphilis Study
• 1932-1972
• Macon County, Alabama
• Supported and conducted by the US Public Health Service
• 600 black men enrolled– 399 with syphilis
– 201 without syphilis
• Told that they would receive treatment for “bad blood”
• Examinations, blood, CXR, spinal taps
• Received free medical examination, medication (not for syphilis) and burial insurance
Tuskegee Syphilis Study
• Never told purpose of study
• Never given treatment for their syphilis– Until 1945, mercury and bismuth – not very effective and
high toxicity
– 1945 – PENICILLIN is drug of choice
• Estimated that 28-100 died from syphilis
• Concern raised re: possibility of study subjects passing syphilis on to the sexual partners and to their children in utero
Tuskegee Syphilis StudyTime-line
1895: Booker T. Washington gains support for black economic devop’t
1926: Health seen as inhibiting development: Syphilis is major problem
1929: Aggressive treatment program initiated
1931: Support withdrawn s/p Wall St. crash. Decision to follow untreated men in order to show need for treatment program
1932: F/u effort organized into PHS study
1934: First paper showing effects of untreated syphilis
1940: Efforts made to hinder subjects from receiving treatment
Tuskegee Syphilis StudyTime-line
1945: Penicillin is treatment of choice
1947: USPHS sets up “Rapid Treatment Centers” – syphilis declines. Men in study not treated
1968: Concern re: the ethics of the study
1969: CDC reaffirms need for study and gains medical society support
1972: News headline
Study ends
Tuskegee Syphilis StudyTime-line
1945: Penicillin is treatment of choice
1947: USPHS sets up “Rapid Treatment Centers” – syphilis declines. Men in study not treated
1968: Concern re: the ethics of the study
1969: CDC reaffirms need for study and gains medical society support
1972: News headline
Study ends
Jesse Gelsinger Ellen Roche
U. Penn - Gene Transfer
• 18 year old: OTC Deficiency
• Phase I study:
– Dose escalation - “corrective” gene on
adenoviral vector
– Preferential female enrollment
– Stopping criteria - determined by
investigators
U. Penn - Gene Transfer
• Immediate development of fever, rigors
• Rapid multi-system failure
• Death
– Related to adenovirus?
– Related to gene transfer?
– Related to intra-hepatic artery infusion?
– Other?
• Gelsinger – UPENN– Conflict of Interest
– Data and Safety Monitoring Plans
– Adverse Event Reporting
– Informed Consent
– Sanctions
UPENN/CNMC and the Justice Dept– Alleged:
• investigators “misrepresented the clinical findings of the study in submissions to NIH, FDA and IRBs...”
– Three investigators: • Must complete education and training
• 3 year clinical research restriction – must have a medical monitor
– Principle Investigator• Cannot be a sponsor of an FDA-regulated trial
for 5 years
– Fines: PENN: $517,496
CNMC: $514,622
JHU: Chronology
May June6 7 8 9 17 2 6
Death Reported
Study suspended
Subject completed hexamethonium inhalation
Subject: SOB on exertion, myalgias and fever
Subject hospitalized: serious adverse event reported
Subject Died
JHU: Chronology
June July6 19 21 22
OHRP suspends JHU MPA
and orders suspension of all
human subjects research
Death Reported
JHU submits itemized
response to OHRP
OHRP accepts response:
allows resumption of
some research
• Ellen Roche – Johns Hopkins University– Drug review and INDs
– Adverse Event reporting
– Process of IRB review
Why the IRB does what it does
• Federal and state laws
• Case Law
• Condition of Grant Award
• The Boston Globe
Federal and state lawsCase Law
Condition of Grant AwardThe Boston Globe
• Age discrimination
• Ban on human embryo research
• Stem Cell guidelines
• Confidentiality of medical records
• Conflict of interest
• Human Subjects Protections
• Inclusion of Children
• Inclusion of Women
• Misconduct in Science
• Seat belt use
Why the IRB does what it does
• Federal and state laws
• Case Law
• Condition of Grant Award
• The Boston Globe
Federal and state lawsCase Law
Condition of Grant Award
The Boston Globe
“Gene Research Kills Teenager”(Washington Post 7/2/2000)
“Researchers Fake AIDS Study Data”
(Washington Times 12/5/03)
Research at US Veteran’s Hospitals Nationwide Under Investigation
(NYT 4/13/03)
Federal and state lawsCase Law
Condition of Grant Award
The Boston Globe
“the fundamental flaw or limitation of IRBs is that it’s always been the
researchers who are in effect regulating themselves. Some people paint that as a strength –’who else has this kind of information?’ But we need to start exploring models that reduce that
conflict.”
Public Citizen’s Health Research Group
Federal and state lawsCase Law
Condition of Grant Award
The Boston Globe
“What we had with Ellen Roche and Jesse were avoidable errors. If these people had done the basic science correctly, Ellen and Jesse
wouldn’t have died. Our oversight of experiments on humans is woeful. There is no system in place to sanction these people. All there is is basically a slap on the wrist.”
Paul Gelsinger
The End