# Presentation: 522776

## Ethical and practical considerations of paying research participants

- Christine Grady
- Department of Clinical Bioethics
- Clinical Center/NIH

## Example

- Phase 2 study of a new anti-anxiety drug for those with high levels of stress on a validated screening instrument, no current anti-anxiety drugs, and no significant medical problems.
- Involves several blood draws, physical exams, and hour-long interviews over the course of six months.
- Participants will be paid $500 on completion of the study.

## Example

- Comparison of a long-lasting formulation of an antihypertensive drug and the standard version to see if the new version improves adherence.
- The participants are already taking the standard formulation and there are no additional risks.
- They will be paid $25 each visit for a blood pressure check and other basic tests.

## Example

- Study of neurophysiologic correlates of anesthesia in healthy volunteers
- EEG, serial bloods, and multiple diagnostic tests after the administration of different anesthetics at each of 4 or 5 clinic visits
- Compensation offered is pro-rated by visit, with total about $2000

## Men's Sexual Health Research
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If you qualify, you will receive financial compensation of up to $1350. You will also receive all study-related care and services. 
Please contact us today

**Men's Sexual Health Research**
- Our physicians are studying the effect of an investigational oral medication on sperm function. If you are between the ages of 25 and 64, are in good general health, and have not had a vasectomy, we may need your help.
- If you qualify, you will receive financial compensation of up to $1350. You will also receive all study-related care and services.
- Please contact us today

## Ads in Real Life: Bar Coaster

- Research Subjects Wanted
- Earn $50-$1295
- Call
- 555-555-5555
- Christine’s Research Institute

## To pay or not to pay?

## Walter Reed

- Paid $100 in gold for participation.
- $100 bonus for successful infection with yellow fever.
- Payable to family in the event of death.

- http://etext.lib.virginia.edu/healthsci/reed/commission.html#vol

**Notes:**
Likely more familiar than St. Martin and Beaumont, this picture shows Walter Reed in Cuba in 1900 with the group of research subjects that he used in his work on Yellow Fever.
Reed paid each subject, most of whom were Spanish immigrants to Cuba, $100 in gold, with a $100 bonus if they were successfully infected.  Incidentally, were anyone to die, the amount would be paid to their family after death.

I cite these historical examples to illustrate that paying research subjects is far from a new practice.  However, it has surely grown in recent years with rapid rate of research in general.

## How common is it to pay research participants?

- Advertisements in newspapers, the internet, and in hallways
- Most research organizations and academic medical centers pay at least some participants (24- 80%*)
- Paying studies range from short term physiologic studies to long term phase 3 clinical trials
- *Dickert et al. Annals 2002

## Table 1.  Types of Paying Studies and Types of Subjects 

| Studies By Type Of Subject Enrolled |  |  | Type of Study  |  |  |  |  |  |  | Total |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  |  | Phase 1 | Phase 2 | Phase 3 | Phase 4 | Physiologic | Behavioral | Other |  |
| Studies That Enrolled Only Healthy Subjects   |  |  | 16 | 5 | 1a | 1b | 37 | 35 | 18 | 113 (24%) |
| Studies That Enrolled Only Patient-Subjects |  |  | 10 | 52 | 97 | 35 | 21 | 39 | 32 | 286 (61%) |
| Studies That Enrolled Both Types Of Subjects  |  |  | 0 | 1 | 2c | 0 | 30 | 8 | 27 | 68 (15%) |
| Total   |  |  | 26  (6%) | 58 (12%) | 100 (21%) | 36   (8%) |  88 (19%) |     82    (18%) | 77  (16%) | 467 (100%) |
|  |  |  |  |  |  |  |  |  |  |  |

- a This phase 3 study was testing a preventive vaccine in uninfected persons
- b This phase 4 study was testing a fiber supplement in healthy subjects
- c One of these studies was evaluating an intervention to reduce heterosexual transmission of herpes simplex and enrolled both the healthy uninfected partner and the patient with herpes.  The other was evaluating an intervention in ADHD and enrolled some healthy children as controls.
- Grady et al. *Cont. Clinical Trials* 2005

## Payment in the U.S.

- .
- Significant variation within and between institutions in amount of payment for particular procedures, inpatient days, outpatient visits.
- Rarely itemized.
- e.g. MRI with contrast 0-$25-$150
- Wide variation in multi-site studies.
- Up to $840 difference for the same study.
- Grady et al. *Cont. Clinical Trials* 2005

**Notes:**
There are several other findings that I want to point out.  First, only 8 of 32 institutions, of all types, had any particular guidance regarding how payment ought to be done, a fact reflected in the lack of description in most protocols for how payment was arrived at or itemization of what payment is for.

Second, there was significant variation, both within and between institutions, in the amount of payment offered for particular procedures, inpatient days, and outpatient visits.  For example, when itemized, the payment for an MRI scan with contrast ranged from $25-$120.

Finally, there was wide variation (up to $840) among payment offered at different sites for the same study in multi-site studies.

## Why pay research participants?

- Facilitates Recruitment
- Helps make participation a revenue-neutral experience
- Compensation for time and contribution
- Incentive to overcome barriers

## Slide 13

## Why pay research participants?

- Money enables participation and can be a sign of respect
- “It is reasonable to pay someone for their work. If you gain, how much are you gaining?  Telling someone their community is gaining is a stretch.  How much time does it take? Time is money. What is the value of time for the person in the study?”

## To what extent does payment facilitate recruitment?

- Data on survey response rates
- Small amounts of money (e.g. $5) increase response rates
- Asch et al. *Med Care* 1998
- Church *Public Opinion Q* 1993
- Doody et al.  *Am J Epidemiology* 2003
- Ulrich et al. *Nursing Research* 2005
- Data on hypothetical willingness to participate
- Money increases willingness to participate
- Halpern et al *Arch Int. Med* 2004
- Bentley and Thacker *J Med Ethics* 2004

## Does money enhance recruitment of healthy volunteers?

- Motivations
- Money
- >90% of those surveyed said financial compensation was main motivation for participation
- e.g. Bigorra and Banos 1990; vanGlederen et al 1993; Hassar et al. 1977
- Healthy volunteers also have other motives, including curiosity, altruism, sensation seeking, knowledge, etc.

## Slide 17

## Does money enhance recruitment of patient-subjects for clinical research?

- Motivations:
- Hope of personal therapeutic benefit
- Attention by/ trust of physician
- Knowledge
- Altruism
- Access to care

## Why not pay research participants?Ethical concerns

- Commodification
- Skewed sample
- Coercion
- Undue inducement

## Slide 20

## Worry: Money more attractive to lower income individuals
Results
a skewed sample 
and disproportionate burden on the socioeconomically disadvantaged
DATA???
Who participates in research?
To what extent are subjects in paid studies different?

- Worry: Money more attractive to lower income individuals
- Results
- a skewed sample
- and disproportionate burden on the socioeconomically disadvantaged
- DATA???
- Who participates in research?
- To what extent are subjects in paid studies different?

## Coercion or undue inducement?

- US Code of Federal Regulations require that informed consent be obtained “under circumstances...that minimize the possibility of coercion or undue influence”
- 21CFR.50
- 45CFR.46

## Can money be coercive?

- Coercion is a threat of physical, psychological, or social harm in order to compel someone to do something, such as participate in research.
- Money is an offer or an opportunity, and not a threat of harm.

## Coercion

- Used in many different circumstances.
- Often misunderstood as simply meaning involuntary or under strong influence.
- Because coercion is not a benign accusation, the concept needs clarification and should be used carefully.

**Notes:**
The concern about coercion, as you know, is raised in many different circumstances, and I think it is often misunderstood as simply referring to settings that undermine voluntariness or involve strong influence.

But, because coercion is not a benign accusation, it is a concept that should be clear and used very carefully.

## Coercion is Rare in Research

- Inmate whose care and treatment might be compromised for refusing participation.
- Patient may participate in a study run by his or her physician because of the fear or reality that care is contingent on participation.
- Recommendation: use “coercion” carefully and not regarding payment.

**Notes:**
I want to go a bit further, however.  Not only do I think that payment is not coercive.  In fact, I think that coercion is rare in clinical research in general.
There are some cases where retribution for refusal is conceivable.  For example, it is possible that an inmate may receive poor treatment for refusing to participate in a study conducted in a jail.  It is also possible that a physician may threaten to abandon a patient with whom there is an existing relationship if that patient refuses to participate in a study.  These situations are certainly coercive.
Similarly, I think that it is crucial to recognize the possibility of perceived coercion even in the absence of a true threat.  For example, a patient may participate in a study run by his PCP because the patient fears his care is contingent upon participation.  Even if this threat is not real, it may seem to be real to the patient.
Regarding the concept of coercion, then, I think we need to be very careful in how we use the term and avoid using it regarding payment.

## What is undue influence? (inducement)

- An offer one cannot refuse
- A controlling and irresistible influence
- Strong enough to compel someone  to participate against their interests

**Notes:**
But what about undue inducement.  If incentives are considered ‘offers’
might there not be a worry about make me an offer I can’t refuse.
Offering something that is irresistible even if it requires me to do something I otherwise wouldn’t do.

Why do we worry about this in research?  From OPRR guidebook...

## Why worry about undue influence in research?

- An inducement is undue if it is “...so attractive [that it] can blind prospective subjects to potential risks or impair their ability to exercise proper judgment”
- [or] “prompt them to lie or conceal information that would disqualify them from enrolling--or continuing--in research”
- Official IRB Guidebook OHRP

## Do financial incentives blind prospective subjects to research risks?

- If risks are judged acceptable – is this a misplaced worry?
- Will subjects be asked to accept the same risks without financial incentive?
- Understanding of risks can be evaluated during the process of informed consent
- Limited data suggest payment does not obscure risk perception (eg. Bentley and Thacker 2004)

## Do financial incentives impair judgment?

*Voluntary* decisions are motivated by various factors, often including but not limited to money
- Money is one factor in research decisions of some participants
- Most participants (75%) in one study thought $500 could impair the judgment of others, but fewer (20%) that it would impair their own judgment.
- Casarett et al. *J Gen Intern. Med*. 2002

## Should we worry about undue Inducement?

- An excessively *attractive* offer  that leads people to exercise *poor judgment* about research participation that involves a *risk of serious harm*.
- IRBs should not approve studies that expose subjects to risk of serious harm
- Payment cannot be undue inducement in an appropriately approved study
- 	Emanuel, *J Law Med Ethics*. 2004.

**Notes:**
In the paper that I included in your packet, Zeke Emanuel very helpfully considers these different notions of undue inducement in offering a new definition of this poorly understood concept.  His definition is a 4-part definition that I think is a significant improvement on previous attempts.  On this slide is a paraphrased version of Zeke’s definition.
First, there must be an offered good
Second, the good must be excessively attractive
Third, the offer leads people to exercise poor judgment 
Finally, participation must involve a risk of serious harm.

## Undue Inducement

- Concern about undue inducement misdirected in a study with little risk.
- Concerns about payment obviating voluntariness are counter-intuitive.
- Concerns about problems with consent argue for improving the consent process.
- 	 Emanuel, *J Law Med Ethics*. 2004

**Notes:**
I agree with Zeke’s view that worries about undue inducement seem largely misdirected in studies involving no risk at all.  It seems awfully odd to me, for example, to worry about a study that pays $500 to ask people about their favorite color.
In addition, I think Zeke rightly argues that concerns about voluntariness are counter-intuitive.  After all, it does seem odd to say that someone who makes a decision in order to gain money is acting involuntarily.
Finally, he points out that if the concern is about the quality of consent, the solution should be to improve the consent process and not change payment.

## Undue inducement

- “I’ll know it when I see it”
- Decisions left to investigators and IRBs
- Caution at the ends of the risk spectrum or in settings where subjects might have values that conflict with the research.

- Subjects may be paid for inconvenience and time spent, and should be reimbursed for expenses incurred, in connection with their participation in research; they may also receive free medical services. However, the payments should not be so large or the medical services so extensive as to induce prospective subjects to consent to participate in the research against their better judgment ("undue inducement").
- CIOMS International Ethical Guidelines

## Models for paying research participants

- Market model
- Wage payment model
- Reimbursement model
- Appreciation model

## Models of payment

|  | Market | Wage Payment | Reimbursement
 |
| --- | --- | --- | --- |
| Justification | Incentives  to facilitate recruitment | Compensation for time, effort, uncomfortable procedures | Participation should be revenue neutral |
| Approach
 | Escalate payment to meet recruitment  | Standardized
wage-like payments | Reimbursement of  out-of-pocket expenses
 |

-                                   Dickert, N and Grady, C. (1999)  *NEJM * 341(3):198-203

## Wage Payment Model

- Participation in research requires little skill but takes time, effort, and endurance
- Payment should be based on a wage scale similar to other unskilled jobs
- Pay a standardized hourly “wage”, perhaps augmented by pay for particularly uncomfortable procedures or added inconvenience

## Advantages of Wage Payment

- Greatly reduces the potential for undue inducement
- Provides valuable standardization across studies
- Adheres to the principle of justice by paying similar individuals similar amounts

## Does/should who you are paying matter?

- Patient subjects
- Children

## Payment to research subjects

- Common perception- Only healthy subjects in research are paid, patient-subjects are not
- Why might patient subjects be viewed differently?
- They may benefit from the research
- They are especially vulnerable

## These common perceptions appear not to be true:
75% of paying protocols included ‘patient-subjects’ and paid all or some of them
64% of those studies offered a prospect of therapeutic benefit to the patient-subjects
And, patient subjects are often asked to participate in research or research procedures that offer no prospect of benefit
Grady et al. Cont. Clinical Trials 2005

- These common perceptions appear not to be true:
- 75% of paying protocols included ‘patient-subjects’ and paid all or some of them
- 64% of those studies offered a prospect of therapeutic benefit to the patient-subjects
- And, patient subjects are often asked to participate in research or research procedures that offer no prospect of benefit
- Grady et al. *Cont. Clinical Trials* 2005

## Are patient-subjects more vulnerable?

- Special vulnerability of patients
- “Therapeutic misconception”
- Payment could reduce or eliminate it
- Power differential
- Payment could make it easier to refuse
- Need data

**Notes:**
I am not persuaded by either of these arguments, and I’ll show you why.
Special vulnerability of patients
“Therapeutic misconception”
Payment may reduce or eliminate it
Power differential 
Payment may make it easier to refuse
Patients derive benefit from research
Simply incorrect for many studies
Benefit may make payment unnecessary but should not make payment unethical
No inherent distinction 

## Patient subjects

- For studies with a prospect of benefit, payment may be unnecessary as an incentive; but it does not follow that payment is unethical.
- In contrast, it may be unfair to not compensate or reimburse all subjects for similar contributions or expenses

## Worry: Children do not provide their own consent.  Money could sway parental decision making.

Yet, research can involve cost and inconvenience to parents. And, risk to children in research is carefully evaluated and limited.

Should children and/or their parents receive money or other payment as reimbursement, compensation, appreciation, or incentive??

- Worry: Children do not provide their own consent.  Money could sway parental decision making.
- Yet, research can involve cost and inconvenience to parents. And, risk to children in research is carefully evaluated and limited.
- Should children and/or their parents receive money or other payment as reimbursement, compensation, appreciation, or incentive??

## Some support for at least reimbursing expenses of parents
Some argue compensation for contribution should go to the children 
Child’s age matters
Need more data

- Some support for at least reimbursing expenses of parents
- Some argue compensation for contribution should go to the children
- Child’s age matters
- Need more data

## Forms of Payment

- Payment may come in several forms:
- Money
- Gifts
- Free care
- Travel vouchers
- Gift certificates

## Considerations when deciding whether and how much to pay

- The nature of the study, including study risks and budget
- The nature of participant contributions and vulnerabilities
- Institutional or organizational guidelines
- Local societal and cultural norms

## Practical considerations

- Proposal submitted to the IRB should describe rationale for payment, how dollar amount calculated, and how and when payment will be made.
- IRBs do not consider payment a benefit to offset research risks when deciding to approve a study

## Need for more research

- How does payment affect recruitment?
- What trade-offs do participants make?
- To what extent do people participate in studies they find objectionable or against their interests?
- What are and what determines the sociodemographics of research participants?