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Evaluating Minimal Risk: Time to Adopt a Uniform Standard

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1 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

2 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.

3 “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 (a)6 Waive explanation of available treatment (a)(6)

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

5 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

6 The Definitional Problem Who’s Life is it Anyway?
General Population? Absolute Standard Objective Standard Uniform Standard Subject Population? Relative Standard Subjective Standard Variable Standard

7 History: Uniform Definition
1977 National Commission: Research Involving Children “healthy children” 1977 NPRM proposing subpart D ( FR31786) 1978 HHS Research Involving Prisoners Subpart C (43 FR 53655) “healthy person” 1978 Notice of Proposed Rulemaking for Subpart D (43 FR31786) 1979 NPRM HEW 44 FR for Subpart A “healthy individuals”

8 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)

9 Subpart A Definition 1981 § (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.

10 Response of FDA & OHRP 1981 FDA 21CFR 56 Preamble “healthy individual”
2005 OHRP communication to SACHRP Chair “healthy person” standard

11 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)

12 Who’s Life is it Anyway? 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).

13 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.

14 Objective Metric Fallacy
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).

15 Magnitude & Probability of Harm
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)

16 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.

17 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.

18 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

19 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.

20 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 .

21 Minimal Risk Standard 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 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. 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

22 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.

23 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.

24 Distributive Justice: Research Burdens
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

25 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?

26 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?

27 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.

28 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.

29 Justice Arguments When Research Offers no Prospect of Direct Benefit
Uniform Standard Individuals 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 Standard Persons 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.

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

31 Permissible Greater than Minimal Risk Research with No Prospect for Direct Benefit
Subpart A (a) Risks to subjects are minimized; (b) Risks to subjects are reasonable in relation to anticipated benefits Subpart B § 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 § (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 § 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.

32 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”

33 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.

34 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

35 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)

36 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 hair Oral glucose tolerance test Non-invasive physiological monitoring Modest changes in diet or schedule Vision test Hearing test Neurological exam Tests of fine or gross motor skills Medical and social history including age appropriate questions about sexual activity, drug use, anxiety, depression Personal or Family history Educational interventions for health promoting habits for child, parents, family

37 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

38 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)

39 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.

40 Confidentiality Fallacy
SBER 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.

41 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.

42 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.

43 Guidelines for Determining Minimal Risk (IOM 2004, NHRPAC, 2002; SACHRP SRIC 2005, Fisher, Fried & Panicker, 2005; Fisher, Kornetsky & Prentice, 2006)

44 Guidelines for Minimal Risk Determinations

45 1. Uniform Standard 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)

46 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

47 3. Evidence Based Risk Determinations
Evaluation of risk equivalence should draw on scientific or clinical evidence and avoid conjecture.

48 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)

49 SBER Risk Minimizing Procedures
Economic, Legal Anonymous data Coded Date with secure master list Transcribed tapes Certificate of Confidentiality Dignitary Informed consent Parental or Guardian permission Physical & Psychological Appropriate inclusion/exclusion criteria Appropriate compensation (non-coercive) Psychological Debriefing/or withholding information Counseling Referrals

50 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.

51 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 and Information 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

52 Minimal Risk Decision Criteria
Uniform 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.

53 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

54 Minimal Risk Decision Criteria
Uniform 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.

55 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.


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