# Presentation: 522008

## Risks of Harm & Potential Benefits in Research: A Primer

- Nancy M. P. King, JD
- Department of Social Medicine
- University of North Carolina-Chapel Hill
- nmpking@med.unc.edu

## This Presentation Addresses:

- A typology of risks of harm in research
- A typology of potential benefits in research
- How subjects and investigators think about potential benefits
- How research consent forms describe potential benefits
- Money payments to research subjects
- How IRBs should weigh and balance risks of harm and potential benefits

## Risks of Harm: Categories

**Categories of Possible Harm**
- Harms from receiving the experimental intervention
- Often of greatest concern to subjects
- Often of greatest uncertainty as well
- “Inclusion harms” from study participation
- Examples: limitations on personal care; design inflexibility; schedule

## Risks of Harm: Types

**Types of Possible Harm**
- Physical
- Psychological/emotional
- Legal/economic/social
- Harms to individuals
- Harms to communities and groups
- May be certain (burdens) or uncertain (risks)

## Risks of Harm: Dimensions

**Dimensions**
***Nature ***
***Magnitude***
- size
- duration** **(temporary? permanent?)
***Likelihood***
- Some harms are certain
- Evidence and uncertainty
- Understanding likelihood

## Harms to Groups

- Consideration of possible harms arising from the results of research is explicitly excluded from the IRB’s consideration (45 CFR 46.111(a)(2))
- Increasing awareness of possible harms arising from research results
- Need to address these risks of harm
- In design and initial approval of research
- In review of results
- In dissemination of results
- If not IRB, then who?

## Benefits: Types & Dimensions I

**Direct Benefit**
- resulting from receipt of the intervention(s) being studied
**Dimensions of Direct Benefit**
***Nature***
- clinical endpoint?
***Magnitude***
**size **(improvement? cure?)
**duration **(temporary? permanent?)
***Likelihood ***
- affected by dosage group, design, number of subjects?

## Benefits: Types & Dimensions II

**“****Inclusion” (Collateral) Benefit**
- resulting from being a subject, independent of the studied intervention (e.g., close monitoring, extra free testing or treatment)
**Aspirational Benefit**
** **to society, to science, to future patients

## Eye of the Beholder

- Some possible outcomes may be either harms or benefits:
- often true of “inclusion benefits”:
- additional attention, testing, etc. may be benefit or burden
- opportunity to talk may help or harm
- what’s good/bad for a community may not be good/bad for an individual subject
- IRB, PI, CAB discussion/planning needed

## Discussing Direct Benefit

- Sources of information and discussion:
- Media descriptions of research
- Scientific literature (positive results emphasized)
- Advertisements soliciting subjects
- Research consent forms and the consent process
- Investigators, study coordinators, IRB members, regulatory authorities

## Nature of Direct Benefit

**Contentless (no nature information)**
- “you may or may not benefit”; “personal benefit not guaranteed”
**Surrogate endpoints (statistical ‘stand-ins’)**
- tumor shrinkage; lowered PSA; increased % circulating Factor VIII; growth of new blood vessels; increased CD4+ count
**“****Vague clinical” endpoints (perceptible but not specific)**** **
- feel better; relief of symptoms; improve quality of life; improve immune system function
**Clinical endpoints (clearly perceptible)**
- cure; remission; live longer; improved breathing; fewer infections

## Therapeutic Misconception/ Mis-estimation

- Many subjects misunderstand and/or are misled about:
- the difference between research and treatment
- the nature, magnitude, and likelihood of potential direct benefit
-   e.g., Daugherty et al. (2000) found that 90% of 144 phase I oncology subjects said that they “will get medical benefit from the treatment in this study”

## Informed Consent Project

- Social Construction of Benefit in Gene Transfer Research:
- http://socialmedicine.med.unc.edu/scob

## Interviews: Did Early-Phase GTR Subjects Expect Direct Medical Benefit?

- “Did you expect that getting the gene transfer would improve your condition or help make you better? Would you say yes or no?”
**75% **of subjects answered, **“yes,”** they expected the gene transfer would improve their condition or help make them better.

## Subjects’ Views on Likelihood of Direct Medical Benefit (N=62)

***“... ******the data led me to expect it would help.”***
***“******[PI name] told me it would help...”***

***“... ******hoping it could”***

***“******I’m sure in the back of my mind I hoped but I didn’t really expect it.”***

***“******Absolutely ***_***no***_*** because that’s what they told me.” ***

## What Did They Expect/ Hope For?

**“****Not lose my foot” ****	**
**“****It would decrease the amount of bleeds”**
**	****	****“****Get rid of this cancer in my prostate”**
**	****“****I expected it to help”**
**	****“****Help the blockages in my heart”**
**	****“****If it works, I won’t need radiation”**
**	****“****I was hoping it would have an effect”**

## Interviews: What Did PIs Expect? 

- “Did you expect that the gene transfer intervention in this study would have a direct medical benefit for your subjects?”
- 		    **46% of PIs said, “yes”**
**	****	****    ****54% of PIs said “no”                           ****	****	****or “don’t know”**

## PIs’ Views on Likelihood of Direct Medical Benefit (N=37)

***“******We expected an immune response based on pre-clinical studies.”***

***“...******conceivable but not powered to detect.”***

***“******This is a safety trial not an efficacy trial.”***

***“******It certainly was in the realm of possibility”***

## What Did PIs Expect/ Hope For? 

***Surrogate Endpoints***
**	****Tumor shrinkage**** ****	**
**	****Have the vector produce factor**
**	****Boost the immune system**
**	****Stimulate anti-tumor response**
**	****Grow new blood vessels**
**	****Keep the tumor localized**
***Clinical and Vague Clinical Endpoints***
**	****Longer survival**
**	****Eliminate the pain that they are having**
**	****Decrease severity of infections**
**	****Restore normal circulation**
**	****Avoid amputation**
**	****Decrease symptoms**
**	****Clinical benefit, positive results, therapeutic option**

## Benefit to Society Mentioned?

## Does CF Describe Study as Treatment?

**Treatment Term in Title:  52 (16%)**
**	*****Example: “B1E7 as Treatment for X Disease”***
**Treatment Term in Text:  46 (14%)**
**	*****Example: “If you enroll in this treatment program....”***
**“****Treat” as Verb in Text: 125 (39%)**
**	*****Example:  “20 patients will be treated on this study.”***

## Does CF Offer Direct Benefit to Subjects?

## How Common are “Empty” Benefits?

**“****Empty” Benefit Statements:**
**(No nature content; likelihood indeterminate)**
*You may or may not benefit*
*You may not benefit*
*Personal benefit cannot be predicted*
*Personal benefit cannot be promised*
*Personal benefit cannot be guaranteed*
**Be *****specific and descriptive***** about:**
**	***potential benefits to subjects*
*	**study design*
**Don’t oversell direct benefits; be realistic.**

## Ambiguous Expectations?

**PI**: “Oh, it’s a long shot. It’s a long shot.”
**Q**:  “If you were just to say yes or no what would you say?”
**PI**: “Ah that’s tough, that’s actually, I’m really conflicted about that. I guess if you really push me, I’d have to say no, but I would like to say yes, but I don’t think that would be honest at this point. It’s a little bit too early... to work out.”
**Q**: “I can also punch here ‘don’t know’.”
**PI**: “Well, no, I don’t know. Nobody knows.”
**Q**: “Would you like to answer that instead of yes or no?”
**PI**: “No I’ll put no. It’s the moral response.”

## Belmont on Balancing

- Learning _*what will in fact benefit*_ may require exposing subjects to risk.
- [R]isks to subjects [must] be outweighed by the sum of both the anticipated benefit to the subjects,* *_*if any*_, and the anticipated benefit to society in the form of knowledge to be gained from the research.
- [B]enefits and risks must be “balanced” and shown to be “ in a favorable ratio.” The metaphorical character of these terms draws attention to the _*difficutly of making precise judgments*_....  However, the idea of a _*systematic, nonarbitrary analysis of risks and benefits*_ should be emulated insofar as possible....

## Balancing Harms and Benefits

- You can’t buy risks
- But “coercion” is misused/overused
- First, minimize risks of harm
- Then determine if potential harms are “worth” societal benefit (and individual direct benefit *IF ANY*)
- Then design inclusion benefits as *contextually reasonable incentives *(cf. “fair benefits” concept)

## Paying Subjects

- Is payment a benefit?
- $ vs. inclusion benefits
- Value is in the eye of the beholder
- You can’t buy risks
- “Coercive offers”?
- Proposing a payment requirement
- To underscore research-treatment distinction
- To demonstrate respect for contributions
- To offset inconveniences of participation

## How (Well) Do IRBs Assess and Balance Harms and Benefits?

- IRBs should ask: Is this a fair offer to subjects?
- THEN address subjects’ desire to participate
- Context of the condition and its treatment is important:  What else is available? How well does it work? etc.
- Assessing uncertainty is singularly difficult
- Assessing investigators’ scientific data and claims can stretch IRBs’ capabilities and call for consultants
- IRBs often feel inadequate to the task (van Luijin et al., Ann. Oncol.2002;1307-13)
- IRBs should ask for all the information they need
- Making more explicit assessments and comparisons could promote better use of data and help build expertise