# Presentation: 434803

## Requirements for Ethical Human Research

**A valid and important question**
**Valid methodology**
**Balance between risks/benefits**
**Independent ethical review**
**Informed consent**

*Thanks to Zeke Emanuel*

## Requirements for Ethical Human Research

**A valid and important question**
**Valid methodology**
**Balance between risks/benefits**
**Independent ethical review**
**Informed consent**

## The 

**“****Purpose” **
**of IRBs**

## The global, “motherhood and apple pie” answer:

**The global, “motherhood and apple pie” answer:**

**The purpose of IRBs is to protect human research subjects**

## IRB

**IRB**

**Research Subjects**

## Beecher:

**(In talking about consent)...      ****“A far more dependable safeguard ... is the presence of a truly responsible investigator.”**

## There really are several “purposes” of IRBs;
Many of these can be wrapped together:
	“Helping investigators recognize and address human subjects’ issues in their research”

**Many of these can be wrapped together:**
**	****“****Helping investigators recognize and address human subjects’ issues in their research”**

## Fundamental Constructs:

**Beneficence** (do no harm; do good)
**Justice** (distribute risk and benefit fairly; treat individuals fairly)
**Autonomy / respect for persons** (need for consent)
*These are age-old, but higher profile and more codified in last 50 years*

## Why a Greater Emphasis?

**Education of patients/subjects**
**Public funding**
**News reporting**
**Desire for access**
**Scandal**
**Near misses (thalidomide)**
**Scandal**

## Why a Greater Emphasis?

**High-profile scandals**
- War atrocities ( Nürnberg Code)
- Beecher’s 1966 article: “Ethics and Clinical Research” ***N Engl J Med  *****274:**1354ff [June 16th]
- Tuskegee natural history study of syphilis
*...latter two said problems are  *_***mainstream***_***,          not fringe***

## Why a Greater Emphasis?

**Near misses**
- Thalidomide not licensed in US through a regulatory fluke rather than through having a good process to ensure safety;
- Birth defects in countries where it *was* licensed were a wake-up call

## Results of Scandals and Near-Misses:

- <date/time>

**Results of Scandals and Near-Misses:**

**1962 Amendment to the Pure Food, Drug and Cosmetic Act**
**Helsinki Declaration and other codes of ethics**
**National Research Act of 1974; Belmont Commission & Report**
**Federal research regulations  to protect research subjects**

## Helsinki Declaration:

- <date/time>

**Helsinki Declaration:**

**First edition 1964; several revisions**
**(WMA) Went beyond Nuremberg Code, to address research with therapeutic intent**
**Also addressed diminished competence**
**Called for oversight of research**
***IRBs called “Helsinki Committees” in some venues***

## Helsinki Declaration I(§2):

- <date/time>

**Helsinki Declaration I(§2):**

**...****in an experimental protocol which should be transmitted for consideration, comment and guidance to a specially appointed committee independent of the investigator and the sponsor... **

## Helsinki Declaration I(§2):

- <date/time>

**Helsinki Declaration I(§2):**

**...****in an ****experimental protocol**** which should be transmitted for consideration, comment and guidance to a specially appointed committee independent of the investigator and the sponsor... **

## Helsinki Declaration I(§2):

- <date/time>

**Helsinki Declaration I(§2):**

**...****in an experimental protocol which should be transmitted for consideration, comment and guidance to a specially appointed committee ****independent of the investigator and the sponsor****... **

## 1970: Jean Heller, an investigative reporter for the Washington Star, made public......

**1970: Jean Heller, an investigative reporter for the *****Washington Star, *****made public......**

## Tuskegee:

**Natural history study of untreated syphilis in 400 black men**
**Patients allowed to believe they were being treated**
**New treatments ( *****e.g. *****PCN) neither studied nor offered as they became available**
***PHS funding; PHS researchers, etc.***

## 1974: “Defense of Tuskegee”

***Elliot Richardson ************  Charles McCarthy:***
** *********** ******No***** Effective Defense**
******Need Mechanism to Prevent Recurrence**
**45 CFR §46: Basic DHHS Policy re: Human Subjects**

**Promulgated for NIH: May, 1974**

## 1974: “Defense of Tuskegee”

***Elliot Richardson ************  Charles McCarthy:***
** *********** ******No***** Effective Defense**
******Need Mechanism to Prevent Recurrence**
**45 CFR §46: Basic DHHS Policy re: Human Subjects**

**Several revisions since then**

## 45 CFR § 46:

**Subpart A: **
**“****The Common Rule”**
**Subpart B: **
**Reproductive Issues**
**Subpart C: Prisoners**
**Subpart D: Children**
**Subpart E: Decisionally Impaired (never formally adopted)**

## Also Important:

**Lots of other regs, codes and statutes might apply, depending on the type of research and where it’s done**
**(FDA, JCAHO, VA, local statutes, *****etc*****.)**

## That’s a refresher on the background stuff; now we can talk a bit about the mechanics of dealing with an IRB:

## Institutional Review Boards:

- <date/time>

**Institutional Review Boards:**

**Prospective review of research proposals**
**Continuing review of ongoing research**
**Idea is to protect human subjects from inappropriate risk**
***Ideally a coöperative venture with the investigator, rather than a police function***

## Composition of IRBs:

- <date/time>

**Composition of IRBs:**

**Investigators and Non-investigators**
**People linked to the institution and people independent of it**
**People with useful expertise **(in science, ethics, law, community concerns)
***Ideally a body with a broad background, capable of independent action***

## IRBs ask about scientific merit:

- <date/time>

**IRBs ask about scientific merit:**

**But only in a very narrow way:**

## IRBs ask about scientific merit:

- <date/time>

**IRBs ask about scientific merit:**

**Does the scientific merit warrant putting subjects at risk?**
**Have the risks been minimized insofar as is practicable?**
***General scientific merit review is usually better done elsewhere***

## IRBs ask about conflict of interest:

- <date/time>

**IRBs ask about conflict of interest:**

**But only in a very narrow way:**

## IRBs ask about conflict of interest:

- <date/time>

**IRBs ask about conflict of interest:**

**Is there something that might adversely impact clinical decision making?**
**Is there something that might distort the consent process?**
**Are these bad enough that they need to be disclosed?**
**Is disclosure a sufficient remedy?**

## IRBs ask about conflict of interest:

- <date/time>

**IRBs ask about conflict of interest:**

**Is there something that might adversely impact clinical decision making?**
**Is there something that might distort the consent process?**
**Are these bad enough that they need to be disclosed?**
**Is disclosure a sufficient remedy?**

***Academic misconduct issues re: C-of-I ***
***usually belong elsewhere***

## The most important questions IRBs ask:

- <date/time>

**The most important questions IRBs ask:**

**Are the risks and benefits (personal and societal) in reasonable balance?**
**Is the information and consent process adequate?**

## IRBs also must ask:

- <date/time>

**IRBs also must ask:**

**Does the research conform to federal regulations?**
**How about local ordinances and institutional policies?**
**How about relevant ethical norms?**
**Are there justice concerns re: inclusiveness or vulnerable groups?**

## IRB Reporting Lines:

- <date/time>

**IRB Reporting Lines:**

**To the institution**
**– ****Administratively**
**– ****Maintaining an effective IRB is something the institution guarantees to the feds**
**To the feds**
**Substantively**
**OHRP and FDA**
***Obligations to feds and to subjects may require decisions in tension with institution’s interests***

## It’s crucial to remember:

- We’re all in favor of good science
- We’re all in favor of doing the right thing by research subjects
- We all have things to teach one another
- We’ll do a far better job as colleagues than we will as adversaries

## IRB: Institutional Review Board

**Regulatory Authority---**
**Office of Human Subjects Protection (OHRP)**
**Food and Drug Administration (FDA)**

## Review:

**“...****irrespective of funding source”**

***Not***** just federal monies**

## Important Regulatory Authority

- <date/time>

**Important Regulatory Authority**

***Federal-Wide Assurance of Compliance***
**Institutional agreement with the feds that we will follow the rules**
**Includes the assurance that *****all***** research done at an institution will be done in accordance with federal rules**
**Thus, IRB review is for *****all***** human subjects’ research**

## Important Regulatory Authority

- <date/time>

**Important Regulatory Authority**

**45 CFR §46**
**Basic federal regs covering human subjects**
***AKA***** “OPRR Regs” (historically)**
**	*****AKA***** “OHRP Regs” (currently)**
**Rules establishing and guiding the **_**O**_**ffice for **_**H**_**uman **_**R**_**esearch **_**P**_**rotection**

## Important Regulatory Authority

- <date/time>

**Important Regulatory Authority**

**45 CFR §46**

**Defines “human subject,” “research”**
**Sets standards for IRB composition and function**
**Defines levels of review for different types of research**
**Sets expectations (rules) *****re:***** consent, protections, reporting, special classes of research subjects, *****etc.***

## Important Regulatory Authority

- <date/time>

**Important Regulatory Authority**

**45 CFR §46**

**Defines “human subject,” “research”**
**Sets standards for IRB composition and function**
**Defines levels of review for different types of research**
**Sets expectations (rules) *****re:***** consent, protections, reporting, special classes of research subjects, *****etc.***

**Exempt                Expedited                 Full**

**Review Continuum**

- Level of risk determines
- route of review

## What Needs IRB Review?

** ****Certain research may not need IRB review because it doesn’t meet the *****regulatory***** definition of “research.”**
** ****Certain research may not need review because it doesn’t meet the regulatory definition for involving “human subjects.”**

##  Certain research may be exempt because an individual investigator’s part of the study may be remote from human subjects.

**What Needs IRB Review?**

##  Certain research may be exempt because an individual investigator’s part of the study may be remote from human subjects.
 Certain research may be exempt because it is of such low risk that IRB review would be overkill.

** ****Certain research may be exempt because it is of such low risk that IRB review would be overkill.**

**T****YPICAL**** I****NVESTIGATOR**** P****ROCESS****:  **
***File an abbreviated form with the IRB, in which the claim of exempt status is set forth and explained ... the IRB then decides if it really qualifies as exempt***

**What Needs IRB Review?**

## Exemption Categories:

** ****Federal  regulatory criteria for low-risk research**
** ****Six specific categories of research**
** ****Cannot involve vulnerable population**
** ****Qualifying studies usually  are of short duration**
** ****Cannot create a durable confidentiality risk (no permanent record of individual)**

## Exemption Examples:

** ****Anonymous re-use of data**
** ****Anonymous questionnaires on non-sensitive topics**
** ****Observation of public behavior without recording identities**
** ****Field testing educational strategies or curricula**

## Important Regulatory Issue

- <date/time>

**Important Regulatory Issue**

**Investigator has an inherent conflict in deciding if research is exempt;**
**Investigator, Dept. Chair,***** etc. *****may well not know the regs well enough to make the right call;**
**Regulatory expectation (FDA/OHRP) is that there will be a process for making this decision knowledgeably;**
**At most centers it’s having the IRB office screen for exempt status.**

## Not Quite Exempt:Expedited Review

** ****Federal regulations also recognize that there is some research that is of very low risk, but needs a bit of IRB scrutiny;**
** ****For specific designated categories of risk, IRB review may be carried out by the chair or by an experienced member (rather than by a duly-convened quorum).**

## Not Quite Exempt:Expedited Review

** ****If that experienced member agrees that the criteria are met, full approval may be granted without waiting for the next full IRB meeting;**
** ****Usually is faster, simpler.**

**T****YPICAL**** I****NVESTIGATOR**** P****ROCESS****:  **
***File usual IRB application form with IRB; include consent forms and other supporting info; specifically ask for expedited review (explaining why it would qualify)***

## Important Regulatory Issues

- <date/time>

**Important Regulatory Issues**

**Investigator can request expedited review, but the eligibility call must be made by someone who knows the regs (*****i.e.***** the expedited reviewer);**
**Expedited review is not “review light”; requirements are exactly the same as in full-board review;**
**Difference is (only) that review doesn’t require a convened quorum to grant approval.**

## Full Committee ReviewAnything Else

** ****Vulnerable populations**
** ****Invasive procedures (physically or psychologically invasive)**
** ****Sensitive topics**
** ****Investigational products (FDA)**

## Continuing Review

**Approval expires after a set time period or a set subject accrual**
**Approval cannot be valid for more than one year**
**Re-review has to occur before the approval expires, or there’s a lapse**
**Re-review must be substantive**

## Why Continuing Review?

**Details of studies change**
**Available information changes**
**As a result, risk/benefit balance may change**
**Also as a result, consent burden may change**

## Important Regulatory Issue

- <date/time>

**Important Regulatory Issue**

**It’s the PI’s obligation to get the continuing review info in on time (IRB sends two reminders at our shop);**
**It’s the PI’s obligation to provide all the required information;**
**The regs make no provision for a grace period, so the IRB has no authority to cut a procrastinator any slack. **

## In order to regulate something, you’ve got to define it... 

## So What’s Research?

- <date/time>

**So What’s Research?**

**A systematic activity designed to develop or contribute to generalizable knowledge**
**Note that this is a *****regulatory***** definition**
**Some things we may think of as research don’t meet this standard (*****e.g.***** intramural QA studies)**
***Irony:***** Even if activities carry risk, they may not be required to be subject to oversight**

**45CFR§46.102(e)**

## So What’s a Human Subject?

- <date/time>

**So What’s a Human Subject?**

**A **_**living**_** individual about whom an investigator (whether professional or student) conducting research obtains**** **
**data through intervention or interaction with the individual, *****or***
**identifiable private information.**

**45CFR§46.102(f)**

**Dead folks don’t count, unless the information to be gained has impact for the living (*****e.g. *****relatives) *****(*****who are then the subjects)**

**Unless totally anonymous, any time you have private information you have a human subject... **

## IRBs give special consideration to:

**Vulnerable Subjects:**
**children**
**prisoners**
**mentally disabled persons**
**economically disadvantaged persons**
**educationally disadvantaged persons**

## There are two concerns about vulnerable subjects:

**Do they need special protections because of their vulnerability?**
**Are they being inappropriately excluded from research participation because of their vulnerability?**

## Example: Research Involving Kids

- <date/time>

**Example: Research Involving Kids**

**No more than minimal risk **
**More than minimal risk, but benefit offsets the risk (*****e.g.***** clinical trials)**
**Benefit doesn’t fully offset risk, but risk excess is small and information important for *****the subjects’***** disease or condition**

**45CFR§46: Subpart D**

**Basic idea: take a more conservative view of risk/benefit balance when the subjects are vulnerable**

## IRBs tend to spend a lot of effort on the information and consent process and consent forms:

## Informed Consent:

**What it is:**
**ongoing process of communication and mutual understanding**

**What it isn’t:**
**a piece of paper**
**a moment in time**
**a contract **

## Essential elements for Consent Process and Document:

**Regs list nine features -- the biggies:**
**Must know it’s research;**
**Must know it’s voluntary;**
**Must know what they’re getting into: **
**What’s being asked of them**
**Risks and benefits**
**Alternatives (especially in clinical trials)**

## www.research.umn.edu/irb/

**Help with drafting consent forms**

## Slide 65

## Informed Consent:

**The norm is a written consent form executed prospectively**
**Oral consent may be OK in certain low-risk studies**
**Oral consent may be OK if a written form creates a confidentiality risk**
**Surrogate consent may be OK if risk/benefit balance suitable**

## Problems with IRBs:

**Often too late in the process;**
**Tension between local savvy and institutional conflict of interest;**
**Redundancy in multicenter research**
**Tough to get *****real***** diversity of viewpoint**
**Tough to have sufficient expertise**
**May get bogged down in the most concrete rather than the most important issues**
**Inadequate resources may force into adversarial role**

## IRB

## IRS

## IRS

**IRS**

## IRB

**IRB**

## Slide 72

## Slide 73

## Slide 74