prim&r’s at your doorstep program: irb 250 · 1. discuss concepts, regulatory requirements,...

PRIM&R’s At Your Doorstep Program: IRB 250

Des Moines University 3200 Grand Avenue

Des Moines, IA 50312

PRIM&R’s At Your Doorstep Program: IRB 250 Des Moines University, Des Moines, IA

August 2, 2013

Table of Contents

Page Agenda ………………………………………………………………………………………….............. 1 Continuing Education Information …………………………………………………………………….. 2 Guest Speaker Biography’s …………………………………………………………………………… 3 Presentation Slides

Review of Research Beyond Your Backyard ……………………………………………………. 5 Expedited Review ………………………………………………………………………………….. 23 Internet Research …………………………………………………………………………………... 35 Research with Children and Adolescents ……………………………………………………….. 47

Agenda

8 a.m. Registration and Breakfast 8:20 a.m. Welcome and Introduction 8:30 a.m. Review of Research Beyond Your Backyard 9:30 a.m. Break 9:45 a.m. Expedited Review 10:15 a.m. Internet Research 11:15 p.m. Lunch 12:15 p.m. Case Studies 2:15 p.m. Break 2:30 p.m. Research with Children and Adolescents 3:30 p.m. Questions and Answers Session 4 p.m. Adjourn

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Objectives

Upon completion of this activity, participants will be able to: 1. Discuss concepts, regulatory requirements, and cross-cultural and ethical considerations that an IRB

must consider when the research is conducted beyond the boundaries of its institution, particularly when conducted internationally.

2. Select tools and strategies for acquiring local knowledge of the research setting. 3. Review the federal regulations governing expedited categories, including what types of research are

expedited. 4. Review OHRP Guidance on expedited categories, as well as using expedited review. 5. Review recruiting subjects over the Internet, observation of Internet activity, and collecting data over

the Internet. 6. Consider IRB review issues, including risk/benefit, consent, participation by minors, and privacy and

confidentiality. 7. Discuss electronic data security and IRB review requirements. 8. Analyze the ethical principles as they pertain to subpart D and the regulations. 9. Review what is sufficient pediatric expertise, pediatric risk/benefit assessment and definitions,

parental permission and assent, wards of state, and subpart D documentation requirements. Target Audience

IRB members and chairs, institutional officials, investigators, research compliance officers, vice presidents of research, and support research staff. Commercial Support

Educational grants are not being accepted for this CME activity. Continuing Education Credit

M.D.: This activity has been planned and implemented in accordance with ACCME® Essential Areas and Elements and Iowa Medical Society (IMS) policies. Des Moines University is accredited by the IMS to provide continuing medical education for physicians. Des Moines University designates this live education activity for a maximum of 6.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

D.O.: This activity has been planned and implemented in accordance with the essential areas and policies of the American Osteopathic Association (AOA). Des Moines University is accredited by the AOA and approves this live activity for a maximum of 6.0 hours of AOA Category 2-A CME credits.

D.P.M.: Des Moines University is approved by the Council on Podiatric Medical Education as a sponsor of continuing education in podiatric medicine. Des Moines University has approved this activity for a maximum of 6.0 continuing education contact hours.

Nursing: Des Moines University (provider #112) is approved by the Iowa Board of Nursing as an accredited provider. This activity has been reviewed and approved for a maximum of 7.2 continuing education contact hours. Other: This live activity was designated for 6.0 AMA PRA Category 1 Credits™.

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Guest Speakers

George Gasparis is the president of The PEER Consulting Group, LLC. With more than 30 years of experience in the conduct, administration, review, and compliance oversight of research, Mr. Gasparis provides expert consultation for human research protection programs, institutional review boards (IRBs), and principal investigators/research teams. Before starting the consulting company, he served as the assistant vice president and senior assistant dean for research ethics from 2003 to 2012. In this capacity, he served as the executive director of the Human Research Protection Program and the IRB Office for Columbia University, Columbia University Medical Center (CUMC), and New York Presbyterian Hospital at CUMC. The Columbia IRB Office managed six IRBs that provided oversight for more than 4,500 total active protocols and more than 1,500 new protocols per year. The office also enhanced regulatory compliance through its Compliance Oversight Team and promoted educational training for researchers through comprehensive training programs.

Prior to his arrival at Columbia University in June 2003, Mr. Gasparis was the director for the Division of Assurances and Quality Improvement at the Office for Human Research Protections (OHRP). Prior to his tenure at OHRP from 1996 to 2003, he was the director of the Office of Human Research at The George Washington University (GWU) Medical Center from 1991 to 1996. In that capacity he served as the administrator for the GWU Medical Center IRB, director of the Research Pharmacy, and also served on the behavioral IRB for GWU. Mr. Gasparis also has had extensive experience with clinical trials when he was employed at the GWU Lipid Research Clinic (LRC) from 1981 to1991. During his tenure as data manager at the LRC, he managed more than 40 clinical trials, including the National Institutes of Health awards and studies for 10 different sponsors. Mr. Gasparis is a graduate of GWU. He became a Certified IRB Professional (CIP®) in 2003. Mr. Gasparis indicated he has no financial relationships to disclose relevant to the content of this continuing education activity. Moira Keane, MA, CIP is the former Executive Director of the University of Minnesota, Human Research Protection Program which includes the Institutional Review Boar d (IRB), and the Institutional Biosafety Committee (IBC). The HRPP oversees the research of all University of Minnesota campuses which encompasses review of basic science, clinical research, and social and behavioral sciences projects conducted by faculty, staff, and students. She is actively involved in subjects protections and served as Chair of the AAHRPP Council on Accreditation, as Vice Chair of the Council on Certified IRB Professionals (CCIP), and as a member of the Secretary’s Advisory Committee on Human Subjects Protection (SACHRP) Sub Part A Sub Committee. Ms. Keane indicated she has no financial relationships to disclose relevant to the content of this continuing education activity.

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Review of Research Beyond Your Backyard

George GasparisThe PEER Consulting Group

[email protected]

With recognition to Karen Hansen and David Borasky for

contributions to some slides and content

Learning Objectives• Examine IRB review of research outside your

institution: international, other U.S. locations, and then your cross-town

• International codes, regulations, and guidelines and the application of U.S. standards to international research settings

• Identifying and addressing the challenges of research conducted outside your institution

“You’ve got to be very careful if you don’t know where you’re going, because you might not get there.”

Yogi Berra

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International Research Trends

More global activity prompted by:

• Increase in large-scale public health research -Concentrated in developing countries

• Emerging research markets in China, India, and Eastern Europe/Russia

-Large populations of research-ready potential subjects

• Internet, e-mail, telecommunications

U.S. Research Trends

More research activity prompted by:

• Industry (Pharmaceutical and Device Manufacturers)

• Federal Funding

• Increase in biorepositories/bioinformatics

• Increase in multicenter studies/collaborations

• Internet, e-mail, telecommunications

The application of U.S. research ethics and regulations

when reviewing research outside your institution

(“beyond your backyard”(International or within U.S.)

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Working premise

• The principles of the Belmont Report are generally an appropriate framework for reviewing overseas research

• However, often success is gained by referencing international codes

-Declaration of Helsinki or CIOMS

Belmont Principles and Ethical Basis for U.S. Regulations

• Respect for Persons• Individual Informed Consent• Privacy & Confidentiality• Vulnerable Populations

• Beneficence• Risk/Benefit• Safety Monitoring• Vulnerable Populations

• Justice• Subject Selection• Vulnerable Populations

Respect Overseas

• Autonomy is a western value-Western researchers must not deny autonomy in subjects anywhere

• Community (or family or patriarchy) values-must be respected, particularly during consent

• Autonomy and community can be balanced

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Respect Overseas (cont.)

• A plausible balance: a study is respectful of persons if it is sensitive to their culture• where customs dictate paternal or tribal consent

is appropriate, first obtain such consent

• and, then obtain individual consent

• Still challenging, however, when enrolling women and such consent is not the norm by local customs

Beneficence Minimizing harm to subjects requires

-Good information about potential harm, and cultural conditions, norms, and local laws

-Objective and accurate information about subjects’ lives, social conditions, and other local conditions (e.g., standard practice, other potential risks, etc.)

May require input from multiple sources-Research staff (both sponsor and host country)

-Local IRBs/ethics committees

-NGOs, local governmental agencies, other 3rd parties

Beneficence (cont.)

The special challenge of balancing risk with benefit for those who live dangerous or high risk lives

• Stigmatized groups• sex workers, drug users

• GLB populations

• criminals, gang members, etc.

• Chronically infected persons

• Impoverished persons

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Justice

Who bears the burdens?• Should we be in this country in the first place?

• Objective considerations-Do the subjects come from a group that is affected by the condition being studied?

-Assuming the subjects are among those affected by the condition being studies, are they fully representative of all those affected?

Justice (cont.)

Who bears the burdens?• Rational considerations

-Would a reasonable person agree to participate?

-Would a reasonable third party think it was fair to ask the person to participate?

-Is there some unfair incentive or pressure on the potential subjects that makes agreement likely but unreasonable?

Justice (cont.)

Who benefits from the research?

Individual level

Community level

Post trial access issues

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ABCs of 45 CFR 46Every institution engaged in DHHS-supported or –conducted human subjects research needs:

A. Assurance of Compliance Approved by OHRP

B. Board Approval (i.e., IRB, REB, ethics cmte.)

C. Consent Obtained from Each Subject, Unless Waived by the IRB

D. Disclosure: Reporting of Unanticipated Problems/Risks or Noncompliance

FDA RegulationsAny research involving a drug, device (interventional or diagnostic), or biologic in which the data will be used for supporting marketing approval by the U.S. FDA must comply with the appropriate FDA regulations:

A. Investigational Drugs – 21 CFR 312

B. Investigational Biologics – 21 CFR 600

C. Investigational Devices – 21 CFR 812

All of the above must comply with 21 CFR 50 (Informed Consent) and 21 CFR 56 (IRB Review)

OHRP Guidance –Engagement of Institutions in Research

http://ohrp.osophs.dhhs.gov/humansubjects/guidance/local.htm

-Provides guidance on when one is or is not engaged in human

subjects research.

-One area that guidance is provided is when one is conducting

research vs. providing a service for research

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Are Agreements Necessary?

-IRB Authorization Agreement (IAA)

-Individual Investigator Agreement (IAA)

-Business Associates Agreement (IIA)

-Confidentiality Agreement

-Data Use Agreement (DUA)

-Materials Transfer Agreement (MTA)

-Clinical Trials Agreement

What Makes Clinical Research in Developing Countries Ethical?

E. Emmanuel, et al., What Makes Clinical Research in Developing Countries Ethical? The Benchmarks of Ethical Research, JID 2004:189, 930-936.


E. Emmanuel, et al. (cont’d)

1. Social Value: research must enhance knowledge or health in the research setting

2. Scientific Validity: research design can answer study objectives; study is feasible within the research setting

3. Fair Subject Selection: vulnerability and privilege are not used to determine who joins the trial. Communities for research and subject selection are based on scientific objectives.

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E. Emmanuel, et al. (cont’d.)

4. Favorable Risk Benefit Ratio: risks are minimized; benefits enhanced; and potential benefits to society and the participant outweigh the risks.

5. Independent Review: unaffiliated individuals review the research and approve, amend, or terminate it.

6. Informed Consent: participants should be informed about the research and provide their voluntary consent.


E. Emmanuel, et al. (cont’d)

7. Respect for Participants and Communities: protect privacy, allow withdrawal from the trial, provide new information; monitor well-being; inform them of study results.

8. Collaborative Partnership: respect community’s values; benefits participants/communities; develop the capacity of researchers, the health setting, and the community.

International Codes, Guidelines and Regulations

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Before we go any further!

What does your FWA say you will apply when reviewing research?

• Ethical codes or standards – Belmont? (= “should”)

• Procedural standards – 45 CFR 46? All sub-parts? Regardless of funding source? (= “must”)

• You must do what your FWA says you will do regardless of where the research will be conducted!

Codes, Guidelines, and Regulations

• Code: a system that governs procedure or behavior in particular circumstances or within a particular profession

• Guideline: an official recommendation indicating how something should be done or what sort of action should be taken in a particular circumstance

• Regulation: an official rule, law, or order stating what may or may not be done or how something must be done; an order issued by a government department or agency that has the force of law


• The Nuremburg Code• A product of the war crimes trials prosecuted

following World War II in Nuremburg, Germany.

• Voluntary consent absolutely essential

• Now viewed from a historical perspective

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• The Declaration of Helsinki• Goes further than Nuremburg

• Numerous revisions

• Paragraphs on placebo and post-trial access in 2000 and 2002 versions were contested and subsequently revised

Available in English http://www.wma.net/en/20activities/10ethics/10helsinki/


• CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects• Developing country focus• Vulnerable populations issues• Requires compensation for research related

injury

Available in multiple languageshttp://www.cioms.ch/index.php/publications/printable-

publications?task=mdownload&id=37


• International Conference on Harmonization Guidelines for Good Clinical Practice (ICH GCP)

• Developed by US, Europe, Japan

• Goal = standardize drug development and registration process

Available in English http://www.ich.org/UrlGrpServer.jser?@_ID=276&@_TEMPLATE=254

and Spanishhttp://www.fda.gov/cder/guidance/959fnl-spanish.pdf

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• National Bioethics Advisory Committee Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries• Developing country focus• Viewed through the lens of US requirements

Available in multiple languageshttp://bioethics.georgetown.edu/nbac/clinical/Chap1.html

Codes, Guidelines and Regulations

• The Common Rule & FDA Regs

• Indian Council of Medical Research

• Australia: National Statement on Ethical Conduct in Human Research

• Procedures and Guidelines for the Conduct of Research in Malawi

• Guidelines on Ethics for Health Research in Tanzania

• Terms of Reference for the Regional Committees for Medical Research Ethics, Norway

Application of U.S. Regulations

OHRP has held the position that HHS-supported

international research must comply with 45 CFR

46 and its subparts as its minimum regulatory

standards.

-Exception can only be granted by Secretarial waiver under 101(h) or 101(i)

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Identifying Codes, Regulations, and Guidelines

Practical Approaches:Resources for identifying regulations, policy or law

1. OHRP Website: International Compilation of Human Research Protectionshttp://www.hhs.gov/ohrp/international/HSPCompilation.pdf

2. Harvard School of Public Health Global Research Ethics Map https://webapps.sph.harvard.edu/live/gremap/index_main.cfm?CFID=564576&CFTOKEN=16197342

3. CITI International Training Platform, Module 4: International Studies components entitled: An Overview of International Studies (Appendix A) and Comparison of International Guidelines for Research Involving Humanswww.irbtraining.org

Identifying and addressing the challenges of research conducted

at non-US sites

(BUT, also applies to research outside of your community)

Challenge: Developing Country Settings

G2

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Addressing the Challenges

• Know the environment where the research will be conducted

• Rural or urban

• Type of site (clinic, hospital)

• Site research experience

• Relevant standards of care

Challenge: Study Population

• Research with Non-traditional Vulnerable Populations

• Stigmatized communities

• High poverty

• Illiterate populations

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Addressing the Challenge

• Is research in the population justified?

• Are mechanisms in place to minimize additional risks?

• Confidentiality

• Fair compensation

• Understandable consent / enhancements to the

consent process

Challenges: Informed Consent

• The Application of Western Informed Consent Standards Abroad

• Different beliefs about autonomy

• Role of elders / community leaders

• Translation issues

• Documentation issues


• Ensure the IRB’s understanding of the informed consent process for a study

• Who will obtain consent?

• Where will the consent process take place?

• How long will it take?

• How are translations handled?

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• Ensure the IRB’s understanding of the informed consent process for a study

• Identify local parental permission requirements

• Understand who can give consent for orphans

and other children in unique circumstances

Challenges: Research with minors• Research with Minors

• Local definitions of minor (you may get conflicting answers – document source)

• Research on sensitive topics

• Research with AIDS orphans

• Research with foster

children

Challenges: Local Laws

• Knowledge of local research settings

• Absence of laws/regulations

• Local law versus standard practices

• Varying quality/existence of local IRBs

• Multi-national research = multiple local norms

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• Who will supervise the study when the PI is not there?

• Are there collaborating investigators?

• FWAs? Individual Investigator Agreements? Subcontracts?

• What training will be provided? By whom?


• How will data be brought back to the U.S.?

• Does HIPAA apply?

• Samples brought back? Permit from CDC for infectious agents? (USPHS 42 CFR 71); details on CDC website

• Data Security

• Export Control Laws


Don’t be influenced by stereotypes of a setting or past information that may no longer be true; as demonstrated by the past few slides, the world is changing fast.

Obtain current, objective, and accurate information about a setting, its norms, and customs.

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Obtain a consultant from the setting or with experience of the setting

Establish dialogue with local IRB

Consult with OHRP International Activities staff

Additional StrategiesCreate a supplement to your IRB application

Require attendance at IRB meetings by PI

Require more rigorous/frequent monitoring

Document resources/consultants for review of current study and for future reference

Additional Strategies

Use the CIA website (CIA World Factbook)

https://www.cia.gov/library/publications/the-world-factbook/

Use Google Maps or Google Earth

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References1. C. Milford, et al., Resources and Needs of Research Ethics

Committees in Africa: Preparation for HIV Vaccine Trials, IRB 2006: 28, 1-9

2. E. Emmanuel, et al., What Makes Clinical Research inDeveloping Countries Ethical? The Benchmarks of EthicalResearch, JID 2004:189, 930-936

3. Office for Human Research Protection (OHRP) International

Issues website: http://www.hhs.gov/ohrp/international

4. National Bioethics Advisory Committee…

5. Collaborative IRB Training Initiative – International

Acknowledgement(s)

Karen Hansen, David Borasky

Renee Holt, JD, MPH, RN

Dawn Fitzgibbons, MPH

Wenjin Li, MD, MPH

Steven M. Shaber, JD

Partnership for Enhancing Human Research Protections in Africa

Collaborative IRB Training Initiative -International

Questions & Comments

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Expedited Review

Moira Keane, MA, CIPRetired, HRPP Executive Director,

University of Minnesota

August 2, 2013

Learning Objectives

To review and understand…

Federal regulations that govern expedited review

OHRP guidance and interpretations

Practical tips for using expedited review

Underlying Concepts Some research warrants oversight, but is of

low-enough risk that a full IRB’s attention may be a poor use of resources

Federal regulations therefore allow for some research to be reviewed by less than a full quorum an experienced member or a subcommittee

The criteria for approval are the same; there’s just more flexibility in how review proceeds

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Criteria for the Approval of Research

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Main Criteria (45 CFR §46.111/ 21 CFR §56.111)

(a)(1) – Minimization of risks

(a)(2) – Risk-benefit relationship

(a)(3) – Equitable selection

(a)(4) – Consent process

(a)(5) – Consent documentation

(a)(6) – Data monitoring

(a)(7) – Privacy/confidentiality

(b) – Vulnerable subjects

Consent Process(45 CFR §46.116, 21 CFR §50.20, §50.25)

Intro – Consent process(a)– Required disclosures(b)– Additional disclosures(c)– Waiver #1(d)– Waiver #2

Consent Documentation(45 CFR §46.117, 21 CFR §50.27, § 56.109)

(a) – General(b)(1) – Long form (b)(2) – Short form(c)(1) – Waiver #1(c)(2) – Waiver #2 (Not FDA)The IRB (or reviewer using the expedited

procedure) must determine that criteria delineated in all three boxes are met.

Courtesy of Jeffrey Cooper, M.D.

Federal Regulations45 CFR 46.110 and 21 CFR 56.110

Carried out by IRB chair or one or more experienced IRB members who must be designated by the chair

Reviewers may exercise all of the authorities of the IRB except disapproval i.e., they can either approve or require

modifications to secure approval Any other action (including “deferral”) is not

allowed

All IRB members must be advised of research approved under expedited review

Federal Regulations45 CFR 46.110(b) and 21 CFR 56.110(b)

An IRB may use the expedited review procedure to review either or both of the following:

(1) some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk,

(2) minor changes in previously approved research during the period (of one year or less) for which approval is authorized.

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Caveats Not all minimal risk research is eligible for expedited

review Just because research is in one of the eligible

categories doesn’t mean it is eligible for expedited review

In order to be eligible for expedited review, research must be both on the list of eligible categories and meet the three applicability criteria: No more than minimal risk; and Not be classified research; and If identification of the subjects 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, reasonable and appropriate protections will be implemented so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal.

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.”

45 CFR 46.102(i) and 21 CFR 56.102(i)

Minor Changes Regulations do not define “minor change”

A “minor change” is something that does not alter the risk/benefit balance in an important way

A “minor change” is something that does not alter the consent burden or the ability to get consent in an important way

When in doubt send to full board

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HRPPs should establish criteria for “Minor Changes”

For example:

no substantial alteration in

the level of risks to subjects;

the research design or methodology;

the number of subjects enrolled in the research;

the qualifications of the research team; or

the facilities available to support safe conduct of the research

What it is……….What it is not

Expedited review is a process to review Proposed research

Modifications to previously approved research

Continuing review of research

It is not a process to Handle emergency use

of a test article

Grant exemption determinations

Review serious adverse events/unanticipated problems

Evaluate non-compliance

Categories of Research That May Be Reviewed by the Institutional Review

Board (IRB) through an Expedited Review Procedure

Last revised Nov 9, 1998

http://www.hhs.gov/ohrp/humansubjects/guidance/expedited98.htm

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Federal RegulationsCategories Eligible for Expedited Review

Clinical studies where IND/IDE NOT required

Blood samples (routine methods, small amounts)

Noninvasive prospective collection of biological samples

Noninvasive collection of clinical data

Existing data or specimens, or to be collected for non-research purposes

Voice, video, digital recordings for research

Individual or group behavior, surveys, interviews, oral histories

Selected types of continuing review

Categories in Federal Regulation

(1) Clinical studies of drugs and medical devices only when condition (a) or (b) is met.(a) Research on drugs for which an investigational

new drug application (21 CFR Part 312) is not required. (Note: Research on marketed drugs that significantly increases the risks or decreases the acceptability of the risks associated with the use of the product is not eligible for expedited review.)

(b) Research on medical devices for which (i) an investigational device exemption application (21 CFR Part 812) is not required (includes abbreviated IND devices); or (ii) the medical device is cleared/approved for marketing and the medical device is being used in accordance with its cleared/approved labeling.

Examples

Study comparing Tylenol™ against Motrin™ for simple tension headache

Study comparing patient satisfaction among three brands of compressive sleeve for lymphedema

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(2) Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as follows: (a) from healthy, nonpregnant adults who weigh at least 110

pounds. For these subjects, the amounts drawn may not exceed 550 ml in an 8 week period and collection may not occur more frequently than 2 times per week; or

(b) from other adults and children, considering the age, weight, and health of the subjects, the collection procedure, the amount of blood to be collected, and the frequency with which it will be collected. For these subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml per kg in an 8 week period and collection may not occur more frequently than 2 times per week.

NOTE: OHRP considers withdrawal of blood through an indwelling line to be a venipuncture. OHRP considers each access to an indwelling line to be a venipuncture, not each puncture of the vein.

(3) Prospective collection of biological specimens for research purposes by noninvasive means. *

Examples: urine (no catheter); saliva (no catheter); sputum; stool; buccalswabs; nail clippings; hair clippings; placenta or amniotic fluid at delivery; spontaneously shed teeth.

*nb: this category does not mention intended use of the specimen

4) Collection of data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves. Where medical devices are employed, they must be cleared/approved for marketing. (Studies intended to evaluate the safety and effectiveness of the medical device are not generally eligible for expedited review, including studies of cleared medical devices for new indications.)

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(5) Research involving materials (data, documents, records, or specimens) that have been collected, or will be collected solely for nonresearch purposes (such as medical treatment or diagnosis).

nb: THE COMMA ! It is OK to use expedited review if the materials were generated in a previous research study or in routine clinical care; the idea is that they are not being generated without oversight or specifically for the current study

(6) Collection of data from voice, video, digital, or image recordings made for research purposes.

nb: Subjects might be identifiable from such recordings, so the expedited reviewer must be attentive to confidentiality provisions.

(7) Research on individual or group characteristics or behavior (including, but not limited to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior) or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies.nb: SACHRP has recommended that category 7 should be expanded to more clearly accommodate social, behavioral, epidemiologic, health services and educational research… and related methods Federal Register notice 10/26/07

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“Minimal Risk” without risk This sort of research may have “hidden” or

“soft” risks, like cultural affront or embarrassment

The challenge may be recognizing when there is actually greater than minimal risk, despite a seemingly harmless design

Conversely, we are not obligated to apply the “worst case scenario” to every study

Expedited reviewer needs some social science insight

(8) Continuing review of research previously approved by the convened IRB as follows:

(a) where (i) the research is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions; and (iii) the research remains active only for long-term follow-up of subjects; or

nb: three applicability criteria still apply e.g., long term follow-up procedures cannot expose subjects to greater than minimal risk and the research cannot be classified

(b) where no subjects have been enrolled and no additional risks have been identified; or

nb: Research can be greater than minimal risk. Wording is not “…no subjects have been enrolled since last review…”

(c) where the remaining research activities are limited to data analysisnb: three applicability criteria still apply

(9) Continuing review of research, not conducted under an investigational new drug application or investigational device exemption where categories two (2) through eight (8) do not apply but the IRB has determined and documented at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified.

nb: This means that “Once full board, always full board” is NOT a rigid rule the convened IRB can say “If no surprises, this one’s low enough to be expedited for continuing review.” Cannot be used for classified research.

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“Guidance on the Use of Expedited Review Procedures”

Updated August 11, 2003

http://www.hhs.gov/ohrp/policy/index/index.html

OHRP Guidance

As with review by the convened IRB, expedited review must fulfill all the requirements of review found at 45 CFR 46.111 and subparts B, C, and D, if applicable

IRBs are reminded that the requirements for informed consent (or for altering or waiving the informed consent process or the consent documentation) apply regardless of whether research is reviewed by the convened IRB or under an expedited procedure

OHRP recommends that… documentation include: (a) the specific permissible

categories justifying the expedited review; and (b) documentation of the review and action taken by the IRB Chairperson or designated reviewer and any findings required under the HHS regulations;

written IRB procedures include a description of policies describing the types of minor changes in previously approved research; and

expedited review procedures NOT be used for research involving prisoners. However, if an IRB chooses to use expedited review for research involving prisoners, OHRP recommends that the prisoner representative of the IRB be one of the designated reviewers.

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Practical Tips for Using Expedited Review Procedures

Expedited review is not “Review Lite” All of the regulatory requirements for IRB

review at a convened meeting except voting apply equally to expedited review

Expedited review must be just as thorough as review by the convened IRB

The expedited reviewer must receive all of the information and material that reviewers receive for a convened IRB review

Approval under expedited review requires no further review by the IRB

The full IRB simply needs to be advised of all expedited approvals Most institutions use a simple listing

attached to agendas and/or minutes

Some institutions post the list on an internal IRB website

Essential Documentation

Because there are no minutes, expedited review must be documented in the protocol file, including: the category under which it was approved and the

justification for inclusion under that category

documentation of review and action by reviewer (e.g., review sheet, checklist, etc.)

all findings required in the regulations and protocol-specific findings supporting those determinations

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Summary:

Federal regulations allow for expedited review

In order to eligible for expedited review research must meet all three applicability criteria and be on the list of eligible categories

Expedited review is not “review lite”

References

45 CFR 46 21 CFR 50 and 21 CFR 56 63 FR 60364-60367, November 9, 1998.

“Categories of Research That May Be Reviewed by the Institutional Review Board (IRB) through an Expedited Review Procedure”

OHRP Guidance: “Guidance on the Use of Expedited Review Procedures” Updated August 11, 2003

33

Internet Research

George Gasparis

The PEER Consulting Group

[email protected]

Thanks

Slide template originally developed by

Jeff Cohen, Ph.D. and PRIM&R Staff.

Michael Oakes, Ph.D. is also recognized for contributions on a couple of slides.

Learning Objectives

• Types of Research Activities on the

Internet

• IRB Review Issues

• IRB Review Requirements

35

Types of Internet Research

Research Activities on the Internet

• Recruiting Subjects over the Internet

• Observation of Internet Activity

• Collecting (or transmitting) Data Over the Internet

• Experimental Trials

Observation of Internet Activity, Survey, or Intervention

• Observation (disclosed or undisclosed)

• Gathering information about use of Internet, recording users’ comments• e.g., observation of grieving discussion group,

using “cookies” to track sites visited

• Mining social networking sites for “observational studies”

• Survey

• Lurking or actively manipulating virtual worlds (avatars, second life, etc.)

36

Experimental Trials

• Internet based intervention such as HIV prevention among MSM

• Randomize subjects (recruited from net) to experimental conditions

• Follow subjects and collect data

IRB Review Issues

Recruiting Subjects Over the Internet

IRB needs to review all of the information presented to subjects:

• E-mail invitation and reminder text

• E-mail sender and subject lines

• Mixed media recruitment materials:

-flyers, advertisements, letters, etc.

37

Gathering data over the Internet

IRB needs to review all plans on how subjects will be approached, observed, and how data will be collected and stored

(e.g., data collection forms, instruments, surveys, access to survey web site, details of software, servers, data security plan, etc.)

• IRB issues: consent, confidentiality and participation by minors, data security

Experimental Trials

• IRB Issues?• Recruitment (age?)

• Consent

• Sensitive interventions

• Sensitive questions

• Data protection

• Adverse events

• Bots and other “fakes”

• Payment?

IRB Review Issues

• Research on the Internet presents new concerns to traditional IRB issues of:• Risk/Benefit

• Consent

• Participation by minors

• Privacy & Confidentiality

38

Risk

• Two sources of harm:• participation in the research

• No direct contact with subjects

• Can’t deal with individual reactions(intervention or debriefing)

• breach of confidentiality• Primary source of harm in most Internet

research

Challenges of Internet Research and Effect on Benefits

• Conducting research on the Internet raises concerns about reliability and validity of data

• skewed subject populations

• ease with which subjects can mislead investigators

• difficulty in preventing multiple submissions

• Invalid research can have no benefit.

• inappropriate if any risk to subjects

Consent

• IRBs can waive requirement for consent where appropriate [45 CFR 46.116(d)].

• If consent is required, IRBs can waive requirement for documentation of consent where appropriate [45 CFR 46.117(c)].

39

Consent

• Where consent required but documentation is waived, a “portal” can be used to provide consent information.• Subjects must click on consent page to get to next

page.

• Where written consent required, it is currently not possible to get a signed consent form over the Internet.• Can have subjects submit signed consent form

and get password for access to web site.

Use of electronic signatures for consent or parental permission

• Consider relevant laws in the jurisdiction where the research is going to be conducted.

• Unless the IRB waives a signed consent ,a written consent which may be an electronic version, must be given to and signed by the subjects or LAR

• Must be format that signatures must be legally valid within the jurisdiction where the research is to be conducted.

• OHRP does not mandate a specific method of electronic signature.

Use of electronic signatures for consent/parental permission (cont’d)

• IRBs must adopt technologies and consider

• how the electronic signature is being created,

• if the signature can be shown to be legitimate,

• if the consent document can be produced in hard copy for review by the potential subject.

Example: use of a secure system for electronic or digital signature that provides an encrypted identifiable “signature.” If properly obtained, an electronic signature can be considered an “original” for the purposes of recordkeeping.

(based on OHRP Q&A)

40

Participation by Minors

• Where research qualifies for waiver of parental permission, no additional safeguards are required.• minors can participate without permission • simple statement in consent that

participant is over 18

• Where parental permission required, use options for consent.

Participation by Minors

• To screen out minors:• use Internet Monitoring software (SafeSurf

and Internet Content Rating Association ratings)

• use Adult Check systems• None of these are foolproof

• Since there is no guarantee that minors won’t access research, some research may not be appropriate for the Internet.

Privacy & Confidentiality

• New concerns to traditional IRB issues of privacy & confidentiality

• Privacy concerns• Is activity or are data identifiable?• Constitutes public or private behavior?

• Confidentiality concerns • inappropriate disclosure of information obtained

over the Internet

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Privacy

• Identifiable vs. Anonymous• Online participants usually use

pseudonyms (screen names, handles, etc.)

• Although not publicly linked to actual names, identities can often be “readily ascertained” (e.g., using search engine)

• People’s online identity may be as important to them as their actual identity

Privacy

• Public vs. Private Behavior

• Most online activity is open to the public

• Federal regulations base the definition of “private information” on the subjects’ “reasonable expectation” of privacy

• In many situations (e.g., chat rooms), participants expect privacy and don’t expect their activity to be studied (is there a password?)

• Determination of privacy more complicated than it seems

Anonymity? Are IP addresses identifiable information, like name,

address or SSN?

IP addresses are often critical for internet researchers (they offer evidence of “bot” attacks and so forth).

An IP address does not generally uniquely identify an individual. In some cases, it uniquely identifies a specific computer on the network (which may or may not be used by multiple individuals).

Some IP addresses are used by public access computers or networks in cafes, libraries, etc

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IP Anonymity Solutions

Include in the consent process a brief statement that IP address can sometimes identify specific computers or networks, and that individuals concerned about such identification may wish to use public computers or networks such as those at public libraries, internet cafes, etc.

Any mapping of IP addresses to survey responses should be destroyed after deduplication, payment, and cleaning of the final data set is concluded.

Confidentiality Two potential sources of breach of

confidentiality

inadvertent disclosure Investigator who sent out research database to

entire Listserv

Investigator’s computer was stolen

deliberate attempts to gain access Hacking into research data

Technology can provide reasonable security but cannot guarantee absolute security Some survey tools do not have robust security

Confidentiality

Data transmitted via e-mail cannot be anonymous without the use of additional steps. Almost all forms of e-mail contain the sender's e-mail address. use an "anonymizer" - a third party site that strips

off sender's e-mail address

Web servers automatically store a great deal of personal information about visitors; information can be accessed by others.

43

Confidentiality

Degree of concern over confidentiality depends on sensitivity of the information

Since it is impossible to guarantee absolute data security over the Internet, some extremely sensitive research may not be appropriate for the Internet, but IRBs should weigh risks

IRB Approval Criteria Related to Data Security

• Risks to subjects are minimized by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk.

• Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result.

IRB Approval Criteria Related to Data Security (cont’d)

• When appropriate, there are adequate provisions to maintain the confidentiality of data.

• When appropriate, there are adequate provisions to protect the privacy of subjects.

44

Data Security – How to Minimize Risk Physical Security

• Locked rooms & locked computers

Limited services on computers and up-to-date computer security software

Access authentication• Control access privileges• Strong passwords

Data encryption and firewalls Regular secure backups Secure equipment disposal Adequate technical support and regular security audits

IRB Review Requirements

IRB Review - Key Requirements

Investigators must provide technical information on how to deal with these issues

IRBs need sufficient expertise (or seek expert consultation) on technical aspects of the Internet to ask appropriate questions and evaluate information provided.

IRBs that review Internet research without sufficient expertise are not in compliance with regulations

45

Summary

• Use of the Internet for research is likely to continue to increase

• Research on the Internet presents different concerns to traditional IRB issues

• Electronic transmission and storage of data are key areas for risk analysis

• IRBs need to have sufficient expertise on technical aspects of the Internet in order to ask the right questions and evaluate information provided

Resources

Association of Internet Researchers- Ethical Decision-Making and Internet Research (2012) http://aoir.org/reports/ethics2.pdf

American Psychological Association – Report of the Advisory Group on the Conduct of Research on the Internet (2003) http://www.apa.org/science/apainternetresearch.pdf

American Association for the Advancement of Science --Report on Internet Research (1999)http://www.aaas.org/spp/dspp/sfrl/projects/intres/main.htm

46

Research with Children and Adolescents

Moira A Keane, MA, CIPRetired, University of Minnesota

Human Research Protection Program, Executive Director

Learning Objectives

Become familiar with Historical context for regulations Ethical principles as they pertain to Subpart D Regulations What is sufficient pediatric expertise? Pediatric risk/benefit assessment and definitions Parental permission and assent Considerations for Wards of State Subpart D documentation requirements

Thalidomide Tragedy

47

1962: Kefauver-Harris Amendments Drug amendments of 1962 were enacted in

response to Thalidomide related birth defects Preclinical testing using animals – Required

IND submission to FDA for human studies –Required

Ethical scientific pre-review – Not Required

Informed Consent of Human Subjects – Loosely Required

28 FR 179 (Jan. 8, 1963)

The Landmark Willowbrook Hepatitis Study

Willowbrook Hepatitis Study 1956-1972 Study Site: Willowbrook State School

Subjects: Severely mentally retarded children

Purpose: Study the natural history of hepatitis

Intervention: Subjects were fed viral laden extracts of stool (gg+v and v only).

Potential Risk: Chronic liver disease ( v only )

Potential Benefit: Immunity via a sub clinical infection

Parental Consent: Coerced by admittance restriction

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Congress Reacts to Willowbrook and Other Ethical Lapses

Appointment of The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research marks the beginning of the era of “protectionism”

Public Law 93-348, July 12, 1974

Charge: Determine how to best to protect children who participate in research

Historical Contextearly 1970s

1972: Revelations of the “Tuskegee Syphilis Study”

Anti-war movement strong -- war ending 1973

Individual and Civil Rights Movements active with some results

49

National Commission ReportFR 43 (No. 9), January 13, 1978

The report and recommendations of the National Commission lead to the promulgation of additional protections for children involved in research.

HHS Regulations at 45 CFR 46, Subpart D

Additional Protections for Children Involved as Subjects in Research

FR 48 (No. 46), March 8, 1983effective June 6, 1983

On April 24, 1979 FDA proposed regulations equivalent to the HHS Subpart D.1 The regulation was never finalized and was withdrawn December 30, 1991.21. 44 FR 24106, April 24, 19792. 56 FR 67440, December 30, 1991

“Therapeutic Orphans”

From 1973-1997, the percentage of FDA approved drugs which contained no pediatric labeling was 71-81%.

FDA Status Report to Congress, Jan. 2001

50

Congress and FDA Actions

1997 – Food and Drug Administration Modernization Act (FDAMA), P.L. 105-115, 11-21-97

1998 – Final Pediatric Rule, (63 FR 66632, 12-2-98)

2002 – Best Pharmaceuticals for Children Act (BPCA), P.L. 107-109, 1-4-02

2002 – Final Pediatric Rule (overturned 10-17-02 by U.S. District Court, District of Columbia)

2003 – Pediatric Research Equity Act (PREA), P.L. 108-155, 12-3-03

Pediatric Research Equity Act (PREA) Signed into law December 3, 2003

Mimics the Final Pediatric Rule

Requires pediatric studies of certain drugs and biologics

Authorizes the Pediatric Advisory Committee

FDA Regulations at21 CFR 50, Subpart D

“Interim Final Rule” FR 66 (No. 79), April 24, 2001 effective April 30, 2001

Final Rule FR 78 (No. 38), February 26, 2013 effective March 28,

2013

The Children’s Health Act of 2000 required FDA to ensure that FDA regulated clinical investigations comply with Subpart D by April 17, 2001.

Title XXVII, Section 2701, Children’s Health Act,

(Public Law 106-310), 10/14/2000

51

Current Regulations

DHHS- Protections for Children Involved as Subjects in Research (Subpart D, 45 CFR 46.401-46.409)

Adopted March 8, 1983

FDA- Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products ( 21 CFR 50 and 56)

Final rule February 26, 2013

Ethical Principles in The Belmont Report Beneficence

Do no harm

Maximize possible benefits, minimize possible harms

Respect for Persons

Recognize the autonomy of persons

Protect those with diminished capacity

Informed Consent Process

Justice

Burdens and benefits of research

distributed fairly

Fair and just subject selection

Tension in Belmont Principles

Respect for Persons

Protect Those with Limited Autonomy

Limit Research with Children

Justice

Fair Share Research Benefits

Promote Research in Children

(Tension)

(Equal Moral Force)

52

Definition of Children

46.402, 50.3(o), Children " are persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted” (state, provincial, or tribal law)

For NIH inclusion purposes age is 21

Emancipated/mature minors-state law

Exemptions

46.101 (b) (1) and b(3) through (b)(6) are applicable to research involving children

46.101(b)(2) Exemption for research involving educational tests

is unchanged

Exemption for research involving survey or interview procedures or observation of public behavior does not apply to research covered under subpart , exception observations of public behavior when the investigator does not participate in the activity being observed

Sufficient Expertise on the IRB

FDA 21 CFR 56.107

HHS 45 CFR 46.107If an IRB reviews research that involves a vulnerable population, such as children,…consideration shall be given to the inclusion of one or more individuals knowledgeable about and experiences in working with those subjects

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Composition of the IRB• Pediatric/child/adolescent expertise (scientific, psychological,

social, developmental, emotional)

• Community/public advocacy specific to pediatrics/children/adolescents

• Legal expertise (emancipated/mature minors, who is a guardian, state laws pertaining to consent for drug addiction, sexually transmitted diseases, birth control access, foster care, no child left behind)

• Experts in methods used in pediatric research (blood volume, special pediatric labs, methodology to minimize number of subjects, working within school settings)

National Commission: Principles for Guidance Risk/Benefit

Sliding scale" for research involving children

classified into one of four categories according to the risk and the potential for direct benefit to the child.

as risk-benefit relationship of the research become less favorable, additional requirements must be satisfied.

Inclusion of Children Minimal Risk

[45 CFR 46.404, 21 CFR 50.51]

Greater than minimal risk; with direct benefit[45 CFR 46. 405, 21 CFR 50.52]

Greater than minimal risk/ no direct benefit/ will yield generalizable knowledge

[45 CFR 46.406, 21 CFR 50.53]

Not otherwise approvable but opportunity to understand, prevent or alleviate a serious problem affecting the health or welfare of children Federal Review (RARELY USED)

[45 CFR 46.407, 21 CFR 50.54]

54

No Greater Than Minimal Risk

Category :

45 CFR 46.404

21 CFR 50.51

Requirements:

Parental/GuardianPermission

Child’s assent

Greater Than Minimal Risk: Potential for Direct Benefit Category :

45 CFR 46.405

21 CFR 50.52

Requirements:

Risk justified by benefit

Risk/benefit is as favorable as alternative

Parental/guardian permission, child assent

Greater Than Minimal Risk: No Potential for Direct Benefit; Yield Generalizable Knowledge About Subject’s Disorder or Condition

Category :

45 CFR 46.406

21 CFR 50.53

Requirements: Minor increase over minimal

risk

Intervention presents experiences commensurate with those inherent in actual or expected situations

procedure likely to yield knowledge of vital importance to understanding or alleviating a condition

both parents/guardian permission, child assent

55

Not otherwise Approvable But Opportunity to Understand, Prevent, Alleviate a Serious Problem Affecting the Health or Welfare of Children

Category :

45 CFR 46.407

21 CFR 50.54

Requirements:

HHS/ FDA panel of experts to review

Public Comment

Both parents/guardian permission, child assent

Both Parents’ Permission

Both Parents’ Permission

Assent?Assent?One Parent’s

Permission

Sound ethical principles

Vital importance to subjects’ disorder

or conditionAssent?

One Parent’s Permission

Research on a serious problem

Commensurate with subjects’ experiences

RBR of study = RBR of alternatives

Assent?

HHS or FDA review & approval

Risk = Minor increase over MR

Risk = Benefit to subjects

Risk = No more than MR

Not Approved by Local IRB

46.407 50.54

> Minimal Risk No Direct Benefit 46.406 50.53

> Minimal Risk Direct Benefit 46.405 50.52

Minimal Risk

46.404 50.51

Subpart D Summary

Courtesy of Daniel Nelson, MS, CIP; UNC-CH

Definition of Minimal Risk for Research with Children Subpart A Minimal Risk definition is

specifically referred to in Subpart D Standards 46.404-.406

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.

56

Daily Life: Lack of Definitional Consensus Do risks “ordinarily encountered in daily life” or the

“routine physical or psychological examinations or tests” refer to an absolute standard (e.g., the healthy child) or to a relative standard (e.g., the type of risks to which a particular child or population involved in experimentation are typically exposed). “healthy children” National Commission 1977 Preamble to regulations “relative” to subject “healthy persons” Subpart C 1979 “general population” NBAC 2001 “normal, average children” and “the socially allowable risks

parents permit their normal, health, average children to be exposed to in their ordinary lives.” NHRPAC 2001

normal, average, healthy children living in safe environmentsIOM

SACHRP 2005

Minimal Risk Guidance from Advisory Committees National Human Research Protection Advisory

Committee ( NHRPAC), Institute of Medicine (IOM), Secretary’s Advisory Committee on Human Research Protections (SACHRP) have endorsed the “absolute” interpretation of minimal risk. Risks encountered by normal, average, healthy

children living in safe environments in daily life

Interpretations refer to equivalence of magnitude and probability of risk as those encountered in daily life or routine physical and psychological tests.

Why consider an absolute standard? Children whose lives ordinarily involve greater risk

should not be subjected to greater research risk than other children under the umbrella of the “minimal risk” definition. (e.g., children already taking toxic drugs to treat cancer; children who live in violence- prone neighborhoods)

Children living in unsafe environments may be exposed routinely to risks (i.e., exposure to unhealthy levels of lead), but such risks are neither socially desirable nor ethical when introduced through experimental procedures defined as minimal risk.

57

Suggestions for what may be considered routine physical examinations or tests Well child care is one

reasonable basis for comparison

Routine history taking Venipuncture, fingerstick,

heelstick Urine collection via bag Chest x-ray Bone density test Wrist x-ray for bone age Vision and hearing testing Neurological test Oral glucose challenge Minor diet changes

Suggestions for what may be considered routine psychological examinations or tests

Intelligence testing Mental and motor scales Standard educational tests Tests of social

development Family and peer relations Emotional regulation Feelings of sadness or

hopelessness Class room observation

Suggestions to Determine if Minor Increase Over Minimal Risk Increase in risk is “only slightly” more than minimal.

Documented harms are transient and reversible

There is no, or an extremely small, probability that the stress, discomfort, pain, or harm incurred by the procedure will be experienced as severe by the subject.

The investigator has presented sufficient evidence that the previous two conditions are met for the specific subject population and the qualifications of the research personnel

58

Commensurate

The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations

Commensurate applies to the parents’ and or child’s understanding of the experimental procedures during parental permission and assent not to the level of risk

National Commission "The requirement of commensurability of experience should assist

children who can assent to make a knowledgeable decision about their participation in research based, on some familiarity with the intervention of procedure and effect, the use of procedures that are familiar or similar to those used in treatment of the subjects. It should not, however, be used as a major justification for their participation in research, but rather as one of several criteria regarding the acceptability of such participation”

Suggestion for defining “condition” and “vital”

The intervention or procedure is likely to yield generalizable knowledge about the subjects' disorder or condition which is of vital importance for the understanding or amelioration of the subjects' disorder or condition.

The term condition could be interpreted as referring to a specific (or a set of specific) physical, psychological, neurodevelopmental, or social characteristic(s) that an established body of scientific or clinical evidence has shown to negatively affect children’s health and well-being or to increase their risk of developing a health problem in the future.

Vital importance

For interventions or procedures to be considered of “vital importance” there should be clear and significant scientific evidence that their use is likely to yield generalizable knowledge that would contribute to understanding the etiology, prevention, diagnosis, pathophysiology, amelioration or treatment of the condition or disorder.

59

Consent In Research with Children Parents cannot give true "consent" – legally

only an autonomous person can do that for themselves. But parents can and should be respected in their role as responsible for the child’s welfare.( Parental permission required)

Children cannot give true "consent" – they may not have the legal or cognitive ability to make this decision. But this does not mean they should have no say regarding participation. (Child assent required)

Parental Permission

For minimal risk research (46.404) or risk research with prospect of direct benefit,(46.405) the IRB may allow permission from one parent.

For greater than minimal risk research without the prospect of direct benefit (46.406,46.407) permission from both parents is required unless one parent is deceased, unknown, incompetent or not reasonably available, or when one parent has the legal responsibility for the care and custody of the child.

Assent Affirmative agreement Mere failure to object should not be construed

as assent No specific age: consider maturity and,

psychological, emotional, developmental state Required except when child not capable; age, maturity,

psychological state, coma research presents direct benefit,important to child’s well being, available only in context of research

60

Assent Judgment to determine whether assent is

required is based on protocol risk/benefit assessment

IRB must determine adequate provisions are made for soliciting assent,

Judgment can be made for all children involved in research or for each child as IRB determined appropriate

IRB determines whether and how assent must be documented.

Consider what happens when child turns 18. (reaches age of majority)

Methods to Waive Parental Permission Definition of “Child”

Waiver of consent (subpart A, 46.116 (d) )

Children’s regulations recognize a waiver (subpart , 46.408 (c) )

FDA has not adopted the waivers for parental permission (except in accordance with life threatening conditions, 50.23, 50.24)

Definition of Children46.402, 50.3(o), Children " are persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted.

Determined by state law (mature minors may not be considered children under Subpart D if the applicable law of their jurisdiction permits them to provide independent consent to the treatment or procedures involved in the research)

Emancipated/mature minors- State law(few states specifically address the participation of minors/adolescents who are in research).

61

Waiver of Parental Permission or Assent Under §46.116 (d)- Subpart A

46.116 (d) An IRB may approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent set forth in this section, or waive the requirements to obtain informed consent provided the IRB finds and documents that:

1. The research involves no more than minimal risk to the subjects;

2. The waiver or alteration will not adversely affect the rights and welfare of the subjects;

3. The research could not practicably be carried out without the waiver or alteration; and

4. Whenever appropriate, the subjects will be provided with additional pertinent information after participation.

Waiving Permission Under §46.408 (c) Subpart D

Protocol is designed for conditions or subject population for which parent or guardian permission is not a reasonable requirement to protect the subjects (for example, neglected or abused children), it may waive the consent requirements, provided:

- an appropriate mechanism for protecting the children who will participate as subjects in the research is substituted, and

- the waiver is not inconsistent with Federal, State, or local law.

The choice of an appropriate mechanism would depend upon the nature and purpose of the activities, the risk and anticipated benefit, and their age, maturity, status, and condition.

Some waiver considerations May be appropriate when

Parent/guardian permission would jeopardize subject welfare or fail to provide additional subject protections.

There is a reasonable argument that informing parents may result in harm to the child or

There is a reasonable argument that parent permission may not be in the child’s best interest because of conflicts in parental role as it relates to the research

Laws to consider The Health Insurance Portability and Accountability Act

[HIPAA] http://www.hhs.gov/ocr/hipaa/finalreg.html The Protection of Pupil Rights Amendment [PPRA]

http://www.ed.gov/policy/gen/guid/fpco/ppra/index.html The Family Educational Rights and Privacy Act [FERPA]

http://www.ed.gov/policy/gen/guid/fpco/ferpa/index.html State Laws

62

§46.409 Wards

A ward is 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.

Wards

Children who are wards of the State or any other agency, institution, or entity, can be included in research under §46.406 and §46.407 only if such research is;

related to their status as wards: or conducted in schools, camps, hospitals,

institutions, or similar setting in which the majority of children involved as subjects are not wards

( note §46.406 and §46.407 is research greater than minimal risk with no potential for direct benefit)

Practical issues to consider Physical custody may be different from legal custody. The legally recognized guardian may not be involved

in the day to day life of the ward Different arrangements regarding decision making

(i.e. when child is in foster care, biological parents may still have legal ability to make decisions or state may have legal authority)

Frequent fluctuations in guardianship Transient relationships with guardians, decision

makers Variance among state regulations, if any exist Safety of ward while involved in research requires

appropriate oversight ( appointments, follow-up) which may become difficult and complicated

63

Wards (46.406 & 46.407)

The IRB shall require appointment of an advocate for each child who is a ward, in addition to any other individual acting on behalf of the child as guardian or in loco parentis. One individual may advocate for more than one ward, however they must not be associated in any way with The research

The investigator(s)

The guardian organization

Adolescents Considerations of autonomy and privacy are

essential

Adolescents should be given extensive information and time to consider participation—consider separation of assent and permission processes if dissent “trumps’ permission.

Waivers of parental permission may be appropriate

Re-consent at age of majority to continue long term studies

Additional Documentation Required Pediatric expertise involved in review (Assurance roster,

minutes)

Risk/benefit determination including rationale –(protocol, minutes)

Permission of one or both parents (minutes, tell PI)

If parental permission waived, include justification and how criteria satisfied ( minutes)

Is assent required? Why or why not? IRB approved separate assent forms (minutes, tell PI)

Special provisions for wards, if involved (minutes)

Document consideration of any other special ethical issues (minutes)

64

OHRP Guidance

Special Protections for Children as Research Subjects

http://www.hhs.gov/ohrp/policy/Children/childen.html

Research With Children FAQs

http://answers.hhs.gov/ohrp/categories/1570

Children Involved as Subjects in Research: Guidance on the HHS 45 CFR 46.407 ("407") Review Process

http://www.hhs.gov/ohrp/policy/populations/guidance_407process.html

FDA References

Final Rule : Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products

http://www.gpo.gov/fdsys/pkg/FR-2013-02-26/pdf/2013-04387.pdf

Guidelines for Adolescent Health Researchhttp://www.adolescenthealth.org/PositionPaper_Guidelines_for_a

dolescent_health_research.pdf

65

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