Evaluating Minimal Risk: Time to Adopt a Uniform Standard

Celia B. Fisher, Ph.D.Marie Ward Doty Professor of Psychology

Director Center for Ethics Education

Fordham University

November 16, 2006

Annual HRPP Conference, Washington DC

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The Significance of the Minimal Risk Classification

• “Minimal Risk” is a regulatory “sorting” or “gateway” mechanism that permits IRBs to waive certain human subject protection requirements and approve certain types of research with vulnerable populations.

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“Minimal Risk” Classification Permits IRBs to:

Expedite review of research (Protocol is reviewed by IRB Chair or subset of IRB members assigned by chair instead of by the full IRB) (46.110)

Waive some or all informed consent requirements (46.116(d)

Waive signed consent form (46.117c)

Waive explanation of available compensation 46.116(a)6

Waive explanation of available treatment 46.116(a)(6)

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“Minimal Risk” Classification Permits IRBs to:

Approve research involving pregnant women and fetus that hold out no prospect of benefit (Subpart B)

Approve research involving prisoners that study the possible causes, effects, and processes of incarceration, of criminal behavior, prisons as institutional structures or prisoners as incarcerated persons (Subpart C)

Approve research involving children that does not hold out the prospect of direct benefit (Subpart D, 46.404)

Critical baseline for approval of higher risk “non-beneficial” research involving children §§ 46.406 & 407

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Subpart A Definition

§ 46.102(i)

Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

Applies to Subparts A, B and D

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The Definitional ProblemWho’s Life is it Anyway?

General Population?• Absolute Standard• Objective Standard• Uniform Standard

Subject Population?• Relative Standard• Subjective Standard• Variable Standard

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History: Uniform Definition

1977 National Commission: Research Involving Children “healthy children”

1977 NPRM proposing subpart D (19784 3FR31786) “healthy children” 1978 HHS Research Involving Prisoners Subpart C (43 FR 53655) “healthy person”

1978 Notice of Proposed Rulemaking for Subpart D (43 FR31786)“healthy children”

1979 NPRM HEW 44 FR 47688 for Subpart A“healthy individuals”

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1981 Shift to “Variable” Definition

1981 Preamble 45 CFR 46 Protection of Human Subjects

“In light of the public comments…HHS has reworded the final regulation to reflect its intention that the risks of harm ordinarily encountered in daily life means those risks encountered in the daily lives of the subjects of the research

Subpart D“The terms ‘research’ and ‘minimal risk’ are removed

from this subpart [subpart D] since they appear in subpart A §46.102” (NPRM 48 FR 9814)

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Subpart A Definition 1981

§ 46.102(i) Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

Note. The final rule language does not include specific reference to either a uniform (healthy) or relative (subject of research) standard.

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Response of FDA & OHRP

• 1981 FDA 21CFR 56 Preamble

• “healthy individual”

• 2005 OHRP communication to SACHRP Chair

• “healthy person” standard

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Absolute vs. Relative Objective vs. Subjective:

False Dichotomies

Minimal Risk judgments for SBER can not be absolute (fixed level) or objective (independent of individual judgment)

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There is no absolute definition of “general population.”

“Subject populations” are diverse in experience and susceptibility to harm

Harms encountered in daily life or routine examinations as well as individuals’ reactions to these activities are influenced by differences between and within the general population and subject populations (e.g. age, gender, ethnicity, health, social status).

Who’s Life is it Anyway?

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Probability & Magnitude of Harm

Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

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• There is no objective metric to determine whether the actual probability of experimentally induced harm is equivalent to the daily life or routine examination harm to which it is compared (even if the daily life or routine examination probabilities could be accurately estimated).

Objective Metric Fallacy

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Magnitude & Probability of Harm

Magnitude

● The worst harm that could occur in a study should not be very serious—even if many subjects experience it,

● Just because a serious harm can be imagined does not mean that a project must be treated as more than minimal risk (NRC, 2003)

Probability

● If the harm is serious, then the probability of any given subject experiencing it should be quite low (NHRPAC 2003)

● A high probability harm can be minimal risk provided that the magnitude of the harm is very low (NSF, 2002)

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Lack of Objective or Absolute Metric for Magnitude & Probability of Harm

• When is a procedure with a moderate probability of producing a low or moderate level of harm minimal risk?

• When is a procedure with a low probability of producing a serious harm minimal risk? The magnitude and probability of experimentally induced psychological (and in many instances social)

• Harms are influenced by differences between and within subject populations (e.g. age, gender, ethnicity, health, social status). There can thus be no absolute standard for all populations.

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Minimal Risk Definition: Absence of Risk-Benefit Balance

• IRB determination that research is no more than minimal risk is independent of evaluation of potential benefit.

• There is no mention of benefit in the definition. • A study without prospect of direct benefit can be

expedited and informed consent waived, simply on the basis of an assessment of the probability and magnitude of harm.

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Life-Research Risk Fallacy for Research without Prospect of Direct Benefit

• Harms of Research present no prospect of direct benefit

• Harms of Daily Life or Routine Medical or Psychological Examinations often present the prospect of direct benefit

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Life-Research Risk Fallacy

• People drive cars to get to work or school, shop for food or visit friends knowing risks of a car accident are serious.

• Parents permit their children to play competitive sports with a probability of physical harm because of they believe it builds character and socialize children.

• People attend scary movies because of emotional gratification

• Individuals take stressful tests because they want to get into an academic program, obtain employment, or it might identify a disorder.

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UNIFORM VS VARIABLE STANDARD

• Since minimal risk judgments can not be absolute or objective the debate should rest on ethical justifications for applying uniform vs. variable standard for determining whether research is minimal risk .

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Minimal Risk Standard

AMBIGUOUS STANDARD

Subpart A §46.102(i)

“Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.”

Subpart A and by default Subparts B and D.

UNIFORM STANDARD

“The probability and magnitude of physical or psychological harm that is normally encountered in the daily lives or in the routine medical, dental, or psychological

examination of healthy persons” Subpart C, National Commission(1977) and

SACHRP Subpart D recommendations (normal, average, healthy children living in

safe environments VARIABLE STANDARD

“Minimal risk means that the probability and magnitude of harm is not greater than that encountered in the daily lives of the subjects of the research.”

46cfr45 Preamble

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Distributive Justice

• All persons should have equal access to the benefits and burdens of research

• The benefits and burdens of research should be fairly distributed across all research populations.

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Procedural Justice

• The decision-making criteria for determining whether the magnitude and probability of research harm is minimal risk should be uniformly applied for all research populations.

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When research presents no probability of direct benefit….

Should persons who are exposed to greater risk in their daily lives or routine health procedures be exposed to greater research harms and less

human subjects protections

Distributive Justice: Research Burdens

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The Fallacy of “Is to Ought”

• Are populations exposed to greater risks of daily life and routine examinations less susceptible to physical, psychological, or social risks of research that mimic their experience?

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The Fallacy of “Is to Ought”

• Individuals who live in crime filled environments will be less frightened by a confederate entering a classroom with a gun to test memory.

• Individuals with learning disabilities feel less frustrated by research analogs to academic failure

• Shy individuals deceived that they made a social faux pas are less embarrassed that individuals who are not shy.

• Ethnic minorities are less sensitive to racial slurs because they are more likely to experience them in daily life?

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Compound Risk

• It might be argued that individuals who are exposed to higher levels of risk in their daily lives would be more vulnerable to equivalent research risks.

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Compound Risk

• People who experience greater than average distress in their daily lives, will be asked to experience greater stress in research without the protections of a full-board review and perhaps fully informed consent.

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Justice Arguments When Research Offers no Prospect of Direct Benefit

Uniform StandardIndividuals should not be deprived of IRB protections or

subjected to greater research risk simply because their daily lives or routine examinations are filled with greater risk than healthy persons or those living in safe and free environments.

Variable StandardPersons whose daily lives or routine examinations are

filled with greater risk may receive less IRB protections and be exposed to greater risks so as not to be deprived the knowledge benefits of research.

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Knowledge Benefit Fallacy

Uniform criteria for minimal risk does not preclude research participants from participation in research without the prospect of direct benefit.

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Permissible Greater than Minimal Risk Research with No Prospect for Direct Benefit

• Subpart A 46.111 (a) Risks to subjects are minimized; (b) Risks to subjects are reasonable in relation to anticipated benefits

• Subpart B §46.207 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of pregnant women, fetuses, or neonates.

• Subpart C §46.306 (a)2 (iii) Research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on hepatitis …and on social and psychological problems such as alcoholism, drug addiction, and sexual assaults)

• Subpart D §46.406 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition.

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Informed Consent Fallacy• Populations experienced with harm may have a

better reference for judging increased risk during informed consent.

• Informed consent is not a panacea for variable distribution of research harms.

• IRBs must first decide that is ethically appropriate to subject any member of the population to a particular magnitude and probability of harm. An IRB does not follow the principle of “consumer beware”

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Argument for Uniform Standard

• The experience of harm is not relative• On what basis is it fair to deprive individuals of less IRB protections?

Expedited, waiver of informed consent, some types of non-therapeutic research to which better off individuals will not be subjected.

• Not just that more vulnerable populations are made more vulnerable by research

• Buyer beware• There is no absolute criteria nor objective metric for determining minimal

risk. While some might argue that this speaks to a relative, in fact it is the opposite. It says that given the uncertainty a relative standard increases the probability that more vulnerable persons will be subjected to greater harms and less IRB protections in research with no prospect for direct benefit.

• Given the uncertainties and compounding of harms, IRBs should use as their standard the “safest activities of daily life” Grimes.

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The Minimal Risk Problem for SBR

Documented degree of IRB variability in risk assessment for all protocols for both medical and non-medical procedures (Wendler & Shah,

Variability in assigning similar research protocols to expedited ro full review (SBER report)

Perceived over-estimation of risk for SBER

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Overestimation of Risk

• Just because a risk can be imagined does not mean that it is probable.

• Lack of available examples of SBR minimal risk procedures/protocols.

“Determination concerning the probability of physical harms are often easier to make than those involving the probability of non-physical harms (NBAC, 2001, 72)

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Minimal Risk Routine Medical Procedures NHRPAC, IOM. SACHRP

Venipuncture/fingerstick/heelstick

Urine collection via bag Chest X-ray Bone density test Wrist X-ray for bone age Collection of saliva Collection of small sample of

hairOral glucose tolerance test Non-invasive physiological

monitoringModest changes in diet or

schedule

Vision test Hearing testNeurological examTests of fine or gross motor

skillsMedical and social history

including age appropriate questions about sexual activity, drug use, anxiety, depression

Personal or Family historyEducational interventions for

health promoting habits for child, parents, family

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Index Routine Psychological Tests (SACHRP, 2005)

• Child and adolescent intelligence tests

• Infant mental and motor scales

• Educational tests

• Reading and math ability tests

• Neurological or motor disorder screening

• Social development assessments

• Family and peer relationship assessment

• Emotional regulation scales

• Feelings of sadness or hopelessness scales

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Referents for Risks of Daily Life

• Competitive sports

• Educational tests

• Employment tests

• National surveys

• Video games

• Computer work

• Social interactions (e.g., peers, family)

(Fisher, Fried, Panicker, 2005)

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SBER Risk and Confidentiality

• Much of the risk in social and behavioral science research is related to inadvertent or unintended disclosure.

• An adequate data protection plan can and should reduce the risk of such occurrences.

• The OHRP has clarified that the Common Rule allows institutions and IRBs the flexibility to review and approve appropriately designed confidentiality protections.

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Confidentiality FallacySBER research does not pose confidentiality risks greater than

those encountered in routine medical or psychological examinations.

• Routine medical and mental health examinations have the same if not more confidentiality risks (which is why we have HIPAA and confidentiality ethics codes for the health professions).

• Routine health examinations ask questions about sexual behaviors, drug use behaviors, medical conditions, family relationships, history of sexual or physical abuse all of which if revealed have a probability of social, economic, or legal harms.

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Expedited Review & Confidentiality

Applicability

(C) The expedited review procedure may not be used where identification of the subjects and/or their responses would reasonably place them at risk of criminal or civil liability or be damaging to the subjects financial standing, employability, insurability, reputation, or be stigmatizing, unless reasonable and appropriate protections will be implemented so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal.

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SBER Minimal Risk Fallacy

There is a confusion on the part of the SBER community over restrictions on expedited review and waiver of informed consent imposed by:

• The uniform standard

• Inconsistent IRB judgments, overestimations of SBER harms and failure to restrict risk estimations to evidenced based risks.

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Guidelines for Determining Minimal Risk

(IOM 2004, NHRPAC, 2002; SACHRP SRIC 2005, Fisher, Fried & Panicker, 2005; Fisher, Kornetsky & Prentice, 2006)

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Guidelines for Minimal Risk Determinations

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1. Uniform Standard

1. IRBs should apply a uniform standard (general population*) when assessing whether the probability and magnitude of research harms are no greater than minimal risk.

* Healthy persons living in safe environments (age-indexed for studies involving children)

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2. Equivalent Risk

Research risks should be equivalent not identical to risks of daily life and routine examinations based upon:

Duration Frequency Cumulative Effect Reversibility

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3. Evidence Based Risk Determinations

• Evaluation of risk equivalence should draw on scientific or clinical evidence and avoid conjecture.

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4. Determination of Minimal Risk should include Human Subjects Protections

IRBs should evaluate research risk within the context of the human subjects protections described in the protocol (e.g. risk minimizing procedures, subject exclusion criteria, confidentiality protections, type of compensation)

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SBER Risk Minimizing Procedures

Economic, Legal● Anonymous data● Coded Date with secure

master list● Transcribed tapes● Certificate of

ConfidentialityDignitary● Informed consent● Parental or Guardian

permission

Physical & Psychological● Appropriate

inclusion/exclusion criteria● Appropriate compensation

(non-coercive)

Psychological● Debriefing/or withholding

information● Counseling● Referrals

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5. The Uniform Standard Sets a Risk Ceiling

• The uniform standard sets the upper not lower limits of risk to which subjects can be exposed in research classified as minimal risk.

• Risks that are judged to be minimal for the general population may be greater than minimal for special populations.

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Example 1: College Drinking Prevention Request for Expedited Review

• Purpose. Implementation & evaluation of a training program for Resident Assistants aimed at reducing alcohol consumption in college freshmen campus dorms.

• Participants. College students 18 years or older living in the campus dorms.

• Data collection. Survey questions on alcohol related behaviors and attitudes andInformation from student records on alcohol violations in the dorm and GPA.

• Human subjects protections.

Confidentiality. Student ID #s (no names) separated from surveys immediately following data is entry, Certificate of Confidentiality & appropriate data storage.

Informed consent, voluntary participation, reasonable compensation

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Minimal Risk Decision CriteriaUniform Standard: Questions about about alcohol use are routine in

medical and psychological assessments of young adults.

Equivalence: The magnitude and probability of harm resulting from a confidentiality violation in the research is equivalent to that resulting from a confidentiality violation by a practitioner.

Evidence-based: There is no evidence that asking college students questions about drinking increases drinking behavior.

Human Subjects Protections. The confidentiality protections meet regulatory standards and are equivalent to confidentiality protections provided for alcohol related information obtained in routine medical or psychological assessments.

Special Population Risks: The survey questions address frequency and quantity of alcohol consumption and do not include mental health related items (e.g. questions about suicide or indices of substance abuse [i.e. blackouts]). Students with substance abuse problems are not at greater risk.

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Spousal Abuse: Request for Signed Consent Waiver

• Purpose. Factors contributing to recurrence of spousal abuse when men incarcerated for domestic violence return home.

• Participants. Wives of husbands on parole following incarceration for domestic abuse.

• Data collection. Interview questions about husbands’ past and current abusive threats and behaviors toward spouse or children; family involvement with alcohol, drugs, and illegal activities.

• Human subjects protections.

Recruitment. Wives privately told about study during regular home visit from social worker.

Confidentiality. Interviews conducted in home when husband is absent, code names used, Certificate of Confidentiality, adequate record protections. Investigator argues consent signature would create confidentiality risk.

Informed consent, voluntary participation, reasonable compensation

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Minimal Risk Decision CriteriaUniform Standard: Questions about about domestic violence and child abuse

are not part of daily life or routine in medical and psychological assessments in the general adult population.

Equivalence: The magnitude and probability of harm resulting from a confidentiality violation in the research is greater than harms resulting from a confidentiality violation in daily life or by a practitioner for information shared by the general population.

Evidence-based: There is evidence that the risk of spousal abuse increases when abusive husbands learn their wives have informed others about the abuse.

Human Subjects Protections. Storage of data and the Certificate of Confidentiality are appropriate. However, there is a risk that the husband will learn directly or indirectly about the wives’ discussions with the social worker or agreement to the interviews. There is a possibility of mandatory child abuse reporting.

Special Population Risks: Victims of domestic abuse living with abusive spouses are at greater risk of physical harm than the general population.

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IRB-Investigator Partnership IRBs and investigators are jointly committed to protecting

subjects’ rights and welfare.

IRBs should advise investigators to include in protocols a rationale for the minimal risk classification accompanied by sufficient information about subject characteristics, exclusion criteria, the research design, and human subjects protections to permit IRBs to make evidence based risk determinations.

When investigators provide comprehensive evidence based rationales for minimal risk classification, IRB risk determinations should be grounded in available evidence. If there are unsupported concerns additional information should be sought.