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

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

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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