fully accredited since 2006 September 10 & 12, 2013
Research Involving Subjects with Limited Capacity: IRB Expectations for Recruitment and Consent
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THE QUORUM ADVANTAGE
Quorum Review Regulatory Attorney J. Claire Carbary, JD, CIP
IRB Experience Joined Quorum Review IRB in September 2009 WIRB prior to Quorum CIP certification since 2010 Member of the Northwest Association for
Biomedical Research (NWABR) and Public Responsibility in Medicine and Research (PRIM&R)
Legal Background Juris Doctor from Seattle University Member of the Washington State Bar Association (WSBA) Member of the Health and Corporate Law Sections of the WSBA
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ABOUT THE PRESENTER
Research Involving Subjects with Limited Capacity: IRB Expectations for Recruitment and Consent
Research Involving Children 11 Allowable Research with Children 12 Defining “Child” 16 Recruitment for Research Involving Children 20 Assent 21 Permission 27 Wards 32 Neonates 35
Research Involving Adults Requiring a Legally Authorized Representative (LAR) 37 Allowable Research with Adults Requiring an LAR 38 Determining whether an LAR is Needed 40 Identifying an Appropriate LAR 43 Recruitment for Research with Adults Requiring an LAR 46 Assent 47
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WEBINAR OVERVIEW
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Research Involving
Children “The inclusion of children in research advances the commitment to justice in research by improving our knowledge of, and ability to respond to, the unique needs of children throughout their development” - Canadian Tri-Council Policy Statement (TCPS 2), Ethical Conduct for Research Involving Humans
Category 1: Research not involving greater than “minimal risk”
• “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 examinations or tests.
• Must have adequate provision for soliciting assent of children and permission of parent/guardian
Citation: 21 CFR 50.51, 50.53; 45 CFR 46.404, 46.102(i)
Allowable Research with Children
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Category 2: Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects
• Risks must be justified by anticipated benefits
• Risk-benefit ratio must be at least as favorable as that presented by alternative approaches
• Must have adequate provision for soliciting assent of children and permission of parent/guardian
Citation: 21 CFR 50.52; 45 CFR 46.405
Allowable Research with Children
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Category 3: 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
• Risk must represent a “minor” increase over minimal risk
• The intervention or procedures must present experiences on par with those inherent in their actual or expected “situations”
• Must have adequate provision for soliciting assent of children and permission of both parents/guardian
Citation: 21 CFR 50.53; 45 CFR 46.406
Allowable Research with Children
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Allowable Research with Children Category 4: Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children
• Must be disapproved by the IRB and sent to the Commissioner of Food and Drugs or Secretary of HHS
• IRB must find that research presents a reasonable opportunity to further understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children
• The Commissioner or Secretary (as applicable) must determine the research actually meets one of the previous categories OR must agree with IRB determination about the research and find: o that the research will be conducted in an ethically sound manner, and o Must have adequate provision for soliciting assent of children and
permission of parent/guardian Citation: 21 CFR 50.54; 45 CFR 46.407
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“Quote involving children in research…”
Defining
“Child”
“A person’s a person, no matter how small.”
- Dr. Suess, Horton Hears A Who!
Defining “Child” Children means persons who have not attained the legal age for consent to treatments or procedures involved in clinical investigations, under the applicable law of the jurisdiction in which the clinical investigation will be conducted. Citation: 21 CFR 50.3; 45 CFR 46.402
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• Most states set the age of majority at 18 or over, with some exceptions: o Alabama- Age 19 (Ala. Code § 26-1-1) o Nebraska- Age 19 (Nebraska Revised Statues 43-2101) o Puerto Rico- Age 21 (21 P.R. Laws Ann. Tit. 31 § 971)
State Law & Age of Majority
Nebraska
Alabama
Puerto Rico
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If the protocol inclusion criterion regarding age
indicates “18 and older”, and the research will be in these
jurisdictions, then, the research involves “children.”
• Generally- minors aged 14-15 can consent to medical “treatment” • There may be notification requirements:
o Connecticut: Minors 14 and older may consent to mental health treatment, provided that the parents are notified within five days. See Connecticut Gen. Stat. §21a-110.
Citation: Boonstra, Heather and Elizabeth Nash; Minors and the Right to Consent to Health Care, Guttmacher Institute, Guttmacher Report on Public Policy, August 2000, Volume 3, Number 4 Available at: http://www.guttmacher.org/pubs/tgr/03/4/gr030404.html, accessed 08.26.2013.
State Law & Consent to Medical Care vs. Research
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If the research involves procedures or interventions that are not treatment, it is likely parental permission is needed.
Connecticut
• Payments o Who is paid? o Type of payment?
• Advertisements
o Where are you advertising? o Directed to children or parents?
Recruitment for Research Involving Children
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• Understandability o Is advertisement or recruitment
aimed at children written at an appropriate grade level?
• Therapeutic misconception
ENROLL YOUR CHILD
TODAY!
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Obtaining Assent Children from
Assent means a child's affirmative agreement to participate in a clinical investigation. Mere failure to object should not, absent affirmative agreement, be construed as assent.
Citation: 21 CFR 50.3; 45 CFR 46.402
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What is Assent?
The IRB must determine whether “adequate provisions are made for soliciting the assent of children WHEN…the children are capable of providing assent”
If the IRB determines the capability of some or all of the children is so limited that they cannot reasonably be consulted or that the intervention or procedure involved in the research holds out the prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research, the assent of the children is not a necessary condition for proceeding with the research.
Citation: (21 CFR 50.55(a); 45 CFR 46.408(a)
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When is Assent of Children Required?
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State Laws Regarding Assent for Research • Illinois: Minors must consent when considered “capable.” (405 ILCS 5/2-110 774 Ad. Code 260.1900 (2010)).
• Maine: Subjects between the age of 12-18 must provide consent unless they are unable to do so in addition to parent/guardian consent. (CMR 14-472001 (XI)(H)(3)(c)(2010)).
• Massachusetts: Informed consent cannot be given on behalf of a minor who has refused consent. (105 CMR 700.009(E)(4)).
• California: If subject is older than 7 years or older - must provide consent themselves. (California Health and Saf. Code § 111530 (2012).
California
Illinois
Maine
Massachusetts
The IRB should take into account: • Ages of the participants
• Maturity level
• Psychological state
Citation: 21 CFR 50.55(a); 45 CFR 46.408(a)
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Factors to Consider when determining whether Assent is required
• Written assent forms for ages that would typically be reading
• Reading level should match age-range of participants (might need multiple assent forms)
• Consider including images to explain concepts
• Consider an electronic-based approach to assent
• Signature or not?
Obtaining Assent
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Parental Permission
• The IRB must determine that the permission of each child’s parents or guardian is granted
• For categories 1 and 2 of research involving children - the IRB may determine that the permission of one parent is sufficient, otherwise permission of both parents is required
• The signature of the second parent is not required if that parent is deceased, unknown, incompetent, or not reasonably available
Citation: 21 CFR 50.55 (e); 45 CFR 46.408(b)
Parental Permission
Permission means the agreement of parent(s) or guardian to the participation of their child or ward in a clinical investigation.
Parent means a child's biological or adoptive parent.
Guardian means an individual who is authorized under applicable State or local law to consent on behalf of a child to general medical care.
Citation: 21 CFR 50.3; 45 CFR 46.402
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Permission for Children to Participate in Research
• Legally effective consent of children is required if the research is ongoing (including data collection)
• Remote consent may be needed
• If this is anticipated, develop a consent form to be signed by adolescents that will reach the age of majority during the research
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When Children Become Adults
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Minor Parents • Minor parents are still parents • May not be able to consent for themselves
but can consent for their children. o Delaware: a minor parent may
consent for medical treatment for his/her child (13 Del. C. §707 (2010).
o Maryland: minors who are parents may consent to healthcare treatment. Md. Health Code 20-102-20-104 (2010).
o Minnesota: Minor parents may consent to health care. (Minn. R 952S.3050.)
• This can complicate consent for some studies (example: pregnancy exposure registry that would follow mother and child)
Minnesota Maryland
Delaware
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Research Involving “Wards” Ward means a child who is placed in the legal custody of the State or other agency, institution, or entity, consistent with applicable Federal, State, or local law. Citation: Citation: 21 CFR 50.3; 45 CFR 46.402
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Additional Federal Requirements for Research Involving “Wards” Research that would not provide direct benefit (Categories 3 and 4) is not allowable unless the research meets one of the following requirements:
1. Relates to their status as wards; or 2. Is conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of children involved as subjects are not wards.
Citation: 21 CFR 50.56(a); 45 CFR 46.409(a).
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Research Involving Wards and State Law State laws may provide additional protections for children-further restricting research involving wards of the state.
• Alabama: Juveniles in residential facilities are not permitted to be subjects in medical or pharmaceutical experiments (Alabama- Ala Admin. Code r. 950-1-6-.03 (6)(d))
• New Hampshire: Guardian of a minor cannot consent to experimental treatment of any kind unless approved by order of a court (New Hampshire Revised Statutes Annotated 463:12).
. New Hampshire
Alabama
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Research Involving Neonates • Research involving viable neonates- is subject to the requirements for the standard Subpart D
requirements for research involving children • Research involving neonates of uncertain viability and nonviable neonates is subject to a
number of additional requirements: o Where scientifically appropriate, preclinical and clinical studies have been conducted and provide data
for assessing potential risks to neonates. o Individuals providing consent must be fully informed regarding the reasonably foreseeable impact of the
research on the neonate. o Individuals engaged in the research can have no part in determining the viability of a neonate.
Neonates of uncertain viability. Research must potentially enhance the
probability of survival of the neonate to the point of viability, and any risk is the least possible for achieving that objective, OR
The purpose of the research is the development of important biomedical knowledge which cannot be obtained by other means and there will be no added risk to the neonate resulting from the research; and
Consent of one parent
Nonviable neonates. Vital functions of the neonate will not be
artificially maintained for research; Research will not terminate the
heartbeat or respiration of the neonate; There will be no added risk to the
neonate resulting from the research; The purpose of the research is the
development of important biomedical knowledge that cannot be obtained by other means; and
Consent of both parents (unless one is not available) - consent by LAR is not acceptable
Ramifications of storing tissue/specimens – Data privacy concerns due to limited ability to “de-identify” data
– Genetic markers discovered in the future could identify risk for developing
diseases or conditions – Growing concerns may lead to laws impacting genetic testing-
• Example: Genetic testing on minors can only be performed with the consent of the parent/legal guardian and written informed consent of the minor (Arizona A.R.S. § 12-2803)
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Specimens & Genetic Testing – Research Involving Children
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Research Involving
Incapacitated
“In keeping with the principle of Justice, those who lack the capacity to consent on their own behalf must neither be unfairly excluded from the potential benefits of research participation, nor may their lack of capacity to consent be used to inappropriately include them in research.” - Canadian Tri-Council Policy Statement (TCPS 2), Ethical Conduct for Research Involving Humans
Adults
• Earliest version of the Nuremberg Code only allowed subjects to consent for themselves
• No federal regulatory restrictions on the research in the U.S. Proposed additional regulations in 1978 for research involving the “institutionalized mentally infirm” were never finalized
• The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Guideline for Good Clinical Practice (ICH-GCP) (E6) provides guidance on research involving incapacitated adults
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Allowable Research Involving Adults Requiring an LAR
Citation: National Bioethics Advisory Commission. Research involving persons with mental disorders that may affect decision-making capacity: report and recommendations, December 1998.
Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled:
(a) The objectives of the trial cannot be met by means of a trial in subjects who can give informed consent personally. (b) The foreseeable risks to the subjects are low. (c) The negative impact on the subject’s well-being is minimized and low. (d) The trial is not prohibited by law. (e) The approval/favorable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the written approval/ favorable opinion covers this aspect.
Such trials unless an exception is justified, should be conducted in subjects having a disease or condition for which the investigational product is intended. Participants in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed.
Citation: ICH GCP E6
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Allowable Research Involving Adults Requiring an LAR
“It is generally agreed that a prospective subject’s capacity to decide whether to participate in a particular research project cannot be determined through a general mental status assessment. Instead, investigators must develop and present the specific material relevant to that project and evaluate the prospective subject’s understanding and appreciation of that information.”
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Standards for Assessing Capacity
Citation: National Citation: National Bioethics Advisory Commission. Research involving persons with mental disorders that may affect decision-making capacity: report and recommendations, December 1998.
• Protocol may dictate the tools or process that should be used to assess capacity- for example specific scores on the MMSE
• Should be conducted by the person obtaining consent
• Depending on risk/benefit ratio and other factors- an independent capacity assessment might be warranted
• Evaluate for: – Ability to evidence a choice (express their preference) – Ability to understand relevant information – Ability to appreciate the situation and its likely consequences – Ability to manipulate information rationally
Citation: Bankert, Elizabeth A. and Robert J. Amdur, Institutional Review Board Management and Function, 2nd Edition, Research Involving Adults with Decisional Impairments, 2006. Leo, Raphael J., Competency and the Capacity to Make Treatment Decisions: A Primer for Primary Care Physicians, Prim Care Companion J Clin Psychiatry. 1999 October; 1(5): 131-141.
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Capacity Assessment
• Idaho: “Any person with sufficient intelligence and awareness to understand the necessity of, nature of, and significant risks involved in any medical treatment is competent to consent to the treatment.” (Idaho Code § 39-4502 (2010).
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State Law Definitions of Capacity
Idaho
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Identifying an appropriate LAR Legally authorized representative means an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research. Family member means any one of the following legally competent persons: Spouse; parents; children (including adopted children); brothers, sisters, and spouses of brothers and sisters; and any individual related by blood or affinity whose close association with the subject is the equivalent of a family relationship. Citation: 21 CFR 50.3; 45 CFR 46.102
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State Law and LARs for Incapacitated Adults
• General order of authority for consent o Agent/guardian with authority to make health care decision on person’s
behalf o Spouse /Domestic Partner o Adult children o Custodial parent o Adult sibling o Adult grandchild o Available adult relative with closest degree of kinship
• If there are multiple people at the same level- they generally must all agree (for example- siblings or children) unless one is the designated agent under an advance health care directive
• U.S. jurisdictions with civil unions or same-sex marriage: o Civil Unions: Colorado, Hawaii, Illinois, and New Jersey o Same-sex marriage: California, Connecticut, Delaware, Iowa, Maine,
Maryland, Massachusetts, Minnesota, New Hampshire, New York, Rhode Island, Vermont, Washington and the District of Columbia
o Domestic Partnerships: Nevada, Wisconsin, Oregon, and the District of Columbia (for both same-sex and opposite-sex couples)
Same-Sex Marriage
Civil Unions
Domestic Partnerships
Colorado: If a patient is not competent to provide consent the physician must make efforts to locate as many interested persons (spouse, parent, adult child, sibling, grandchild or close friend) as possible and inform them of the patient’s lack of decision-making authority so the interested persons may select a proxy. (Colorado- C.R.S. 15-18.5-103(3)).
Colorado: Experimental research involving developmentally disabled individuals is prohibited without consent and a non-affiliated interdisciplinary team is consulted (Colorado—C.R.S. § 27-10.5-114 (7)).
Delaware: Restrictions on research involving residents in a state-operated mental health institution include: objective psychiatrist to monitor capacity to provide consent, witness of consent process and documentation with signature on the consent form—special state-run IRB review. (16 Del. C. §5171-5175).
Minnesota: The guardian of a patient at a mental health institution cannot provide consent to research participation unless a court initially grants approval. (Minn. R §952S.3060).
New Jersey: A public guardian for an elderly individual cannot consent to medical experimentation without the permission of the court. (N.J.St. 52:27G-26).
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State Law and Permission for Incapacitated Adults
Minnesota
Colorado
New Jersey
Delaware
• Advertising – Care providers or LARs – Support groups
• Consider Logistics – Payment or services – Ease of access to
sites/parking, etc. • Therapeutic Misconception
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Recruitment for Research Involving Incapacitated Adults
“When a trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the trial with the consent of the subject’s legally acceptable representative (e.g. minors or patients with severe dementia), the subject should be informed about the trial to the extent compatible with the subject’s understanding and, if capable, the subject should sign and personally date the written informed consent.”
Citation: ICH GCP E6, Section 4.8.12
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Assent for Adults Requiring an LAR
• Missouri: Consent cannot be provided if the incompetent adult expressly declines to participate in the research. (R.S.Mo. § 431.064).
• Indiana: Mental Health patients must be informed of the investigator’s credentials, the risks and benefits of participating in the clinical study, and their ability to revoke consent. (Burns Ind. Code Ann. § 16-36-1.5-10).
• New Mexico: Involuntary commitment to a mental institution does not necessarily mean the patient is incapable of providing consent to research. (New Mexico-N.M. Stat. Ann. §43-1-15).
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State Law & Assent from Adults Requiring an LAR
New Mexico Missouri
Indiana
• There are several additional considerations when utilizing proxy consent for research involving children and incapacitated adults in research.
• It is important to be aware of the legal requirements and ethical guidelines when: – Designing research – Developing recruitment, and – Approaching the consent process
SUMMARY
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fully accredited since 2006 September 10 & 12, 2013
Research Involving Subjects with Limited Capacity: IRB Expectations for Recruitment and Consent
