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Complying With Final Rule Revising the Common Rule for Clinical Trials and Human Research

Today’s faculty features:

1pm Eastern | 12pm Central | 11am Mountain | 10am Pacific TUESDAY, FEBRUARY 28, 2017

​ Abram S. Barth, Esq., Ropes & Gray, New York Emily Marcus Levine, Senior Attorney, U.S. Department of Health and Human Services, Rockville, Md. Laura Odwazny, Senior Attorney, U.S. Department of Health and Human Services, Rockville, Md. David Peloquin, Esq., Ropes & Gray, Boston

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Complying With Final Rule Revising the Common Rule for Clinical Trials and Human Research

February 28, 2017

David Peloquin Ropes & Gray LLP david.peloquin@ropesgray.com 617.951.7786 Abram Barth Ropes & Gray LLP abram.barth@ropesgray.com 212.596.9040 Emily Levine Senior Attorney Office of General Counsel HHS Laura Odwazny Senior Attorney Office of General Counsel HHS

Disclaimer – Emily Levine and Laura Odwazny

Disclaimer for Emily Marcus Levine and Laura Odwazny: This presentation does not constitute legal advice. The views expressed are the presenters’ own and do not bind the U.S. Department of Health and Human Services or its operational components.

6

Agenda

I. Common Rule Background II. Effective and Compliance Dates

• III. Changes to Scope
• IV. Key Definitional Changes

V. Exemptions for Secondary Research Use

• VI. Changes to IRB Review Process
• VII. Expedited Review
• VIII. Continuing Review
• IX. Single IRB Review

X. Informed Consent Requirements

• XI. Waiver of Consent
• XII. Intersection with FDA Regulations

7

Background

• The National Research Act (Pub. L. No. 93-348), passed in 1974, created that

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research to identify basic ethical principles that underlie the conduct of biomedical and behavioral research

• The National Commission published the Belmont Report in 1979
• The Belmont Report identified three fundamental ethical principles for all human

subjects research ― Respect for Persons ― Beneficence ― Justice

8

Background

• The National Research Act also empowered the Secretary of the U.S. Department
• f Health & Human Services (then the Department of Health, Education and

Welfare) to promulgate regulations governing federally-funded research – The Secretary shall by regulation require that each entity which applies for a grant, contract, or cooperative agreement under this chapter for any project

• r program which involves the conduct of biomedical or behavioral research

involving human subjects submit in or with its application for such grant, contract, or cooperative agreement assurances satisfactory to the Secretary that it has established (in accordance with regulations which the Secretary shall prescribe) a board (to be known as an “Institutional Review Board”) to review biomedical and behavioral research involving human subjects conducted at or supported by such entity in order to protect the rights of the human subjects of such research (42 U.S.C § 289)

9

Background

• In 1991, the Department of Health and Human Services (HHS) developed a set of

regulations, adopted by 14 other federal departments and agencies, known as the “Common Rule” – 45 C.F.R. pt. 46, subpt. A

• The regulations applied the Belmont Report’s three principles
• Additional protections for pregnant women/fetuses/neonates, prisoners, and

children (45 C.F.R. pt. 46, subpts. B-D)

• These additional subparts are not part of the Common Rule
• Adopted by HHS, but not by all of the other Common Rule agencies and

departments

10

Background

• Shifting landscape of clinical research over the past two decades

― Rapidly evolving technologies have accelerated mobile and computer capabilities, allowing researchers to collect and access troves of data, which may be pooled, mined, analyzed, and shared ― Breakthroughs in biomedical sciences related to genome sequencing and precision medicine ― Increase in biospecimen repositories and tissue banks, accumulating hundreds

• f millions of human samples
• Changing Risks:

― Interventional research often presents the risk of physical harm ― Risks related to information and biospecimen research often implicate subject privacy and confidentiality

11

Background

• In July 2011, HHS issued an Advance Notice of Proposed Rulemaking (ANPRM)

announcing intention to revisit and modernize the Common Rule

• In September 2015, HHS released the NPRM

― The rule contained many controversial provisions, including requiring consent for all research involving biospecimens ― HHS received more than 2,100 public comments

• Final Rule issued January 19, 2017

12

Final Rule’s Effective and Compliance Dates

• Effective Date of Final Rule: January 19, 2018
• General Compliance Date: January 19, 2018
• Compliance Date for Cooperative Research: January 20, 2020
• Caution: like all regulations, possibility of future changes

13

Transition Provisions under the Final Rule: §__.101(l)

• Ongoing Research Begun Prior to January 18, 2018: §__.101(l)(3)
• Begun = initially approved by an IRB, review waived under

§__.101(i)(departmental/agency waiver), or exemption determination made

• Presumption: prior rule applies
• Optional flexibility: revised Common rule applies to a study if:
• institution makes this determination; &
• IRB documents this determination
• Research Begun On or After January 19, 2018: §__.101(l)(4)
• Revised Common Rule applies

14

Effective and Compliance Dates - Commentary

• Dividing line: January 19, 2018

― Research approved or exempted before ― Research approved or exempted after

• Many commenters to NPRM noted significant time and resource investment necessary

to comply with the revised Common Rule

• May require changes to an institution’s or hospital’s clinical settings
• Academic medical centers, hospitals, tissue banks, drug and device companies, and

CROs may not be implementing revised rule just yet because: ― Lag time to understand fully the revised Common Rule and determine what changes will be necessary (in-house capacity: GC, regulatory affairs, compliance; external consultants/counsel) ― Uncertainty about whether the new administration will repeal or modify the revised Common Rule

15

Effective and Compliance Dates (cont’d) - Commentary

• List of minimum activities to reach compliance:

― Revise written IRB procedures ― Train IRB members, researchers, and sponsors on revised procedures ― Revise forms (e.g., consent and protocol templates) ― Update IT systems ― Implement reliable and complete research tracking system

• Transition

― Research approved or exempted before Jan. 19, 2018 that continues after that date may voluntarily become subject to the revised Common Rule ― Purpose is to provide “additional flexibility to regulated entities” ― But what is required?

― Full compliance, including modifying consent forms and reconsenting; or ― Partial compliance with those provisions considered “flexible,” such as the less rigorous continuing review process

16

Final Rule Changes to Scope of Common Rule §__.102(l)(1)-(4)

• Prior Rule & NPRM Proposals
• Final rule: definition of research
• certain carve-outs from definition of research §__.102(l)(1)-(4)

― §__.102(l)(1): certain scholarly and journalistic activities ― §__.102(l)(2): public health surveillance activities ― §__.102(l)(3): collections/analyses for criminal justice or criminal investigative purposes ― §__.102(l)(4): authorized operational activities in support of specified missions

17

Final Rule Changes to Definitions §__.102

• Changes to definitions under human subject: §__.102(e)

― Revised definition of human subject §__.102(e)(1) ― New definition of identifiable private information: §__.102(e)(5) ― New definition of identifiable biospecimen: §__.102(e)(6)

• New provision: reexamination of meaning of identifiable private

information and identifiable biospecimens: §__.102(e)(7)(i) ― Consultation with appropriate experts ― Within 1 year and regularly thereafter (at least every 4 years) ― Collaboration by Common Rule departments and agencies ― Interpretation of terms may be changed

18

Final Rule Changes to Definitions §__.102

• New provision: assessment of whether there are analytic

technologies or techniques that should be considered to generate identifiable private information or identifiable biospecimens: §__.102(e)(7)(ii) ― Consultation with appropriate experts ― Within 1 year and regularly thereafter (at least every 4 years) ― Collaboration by Common Rule departments and agencies ― Any identified technologies/techniques will be included on list published after notice and comment

• New definition of written/in writing - §__.102(m)

― Extends to electronic formats

19

Definition of “Research” - Commentary

• Carve-out for certain “scholarly and journalistic activities”

― Many of these activities were not considered research under the pre-2018 rule because not producing “generalizable knowledge” ― Adds clarity regarding what is and what is not research, which will be particularly useful for humanities and social sciences researchers

― Rather than exclude entire fields of study, the relevant inquiry is whether: ― The research focuses on the specific individuals about whom information is collected, in which case it is excluded from the definition; or ― The research is intended to gather information on individuals in order to make findings that apply to an entire group to which the individuals belong, in which case it is not excluded from the definition

― Certain activities in a given field (e.g., sociology or anthropology) may qualify for the carve-out, whereas others may not

20

Definition of “Research” - Commentary

• Carve-out for “public health surveillance”

― Key is to focus on the purpose of the activity being conducted, i.e., is the activity being conducted solely to permit a public health authority to perform a public health surveillance activity ― May affect private organizations if they are contracted by a public health authority to perform part of the mandated public health surveillance function ― Similar to the provision of HIPAA that permits covered entities to disclose protected health information (“PHI”) for public health activities, e.g., reports

• f adverse events to FDA

21

Removal of Option to “Check the Box” on FWA

• Commentary
• Currently an institution has the ability to “check the box” on its federalwide

assurance (FWA) to apply voluntarily the requirements of the Common Rule to all of its research involving human subjects and subject all such research to the oversight

• f OHRP
• A non-regulatory change of the final rule was to eliminate the option of “checking

the box” on the FWA ― Institutions as a matter of internal policy may decide to continue to apply the Common Rule to all of their human subjects research ― Potential issue for institutions in states such as New York that have laws governing human subjects research that apply when the research is not “subject to” federal regulation ― Timeline of this change is not necessarily tied to the effective date of the Common Rule revisions

22

Change to Definition of “Human Subject” - Commentary

• Continues to differ from HIPAA with respect to what constitutes “identifiable”

information ― Common Rule standard remains whether the identity of the subject may “readily be ascertained by the investigator or associated with the [information/biospecimen]” ― HIPAA has a safe harbor for de-identification involving shedding of 18 identifiers or obtaining expert determination of de-identification

• Much confusion in research community regarding whether genetic information

should be treated as “identifiable” ― New processes for re-evaluating definition of “identifiable” information will allow definition to evolve over time ― List of technologies requiring extra protections will also permit greater clarity for members of the research community

23

Change to Definition of “Human Subject” - Commentary

• Change to policy on newborn dried blood spots (DBS)

― Newborn Screening Save Lives Reauthorization Act of 2014 (the “Act”) required that federally funded research involving newborn DBS collected on or after March 18, 2015 be considered non-exempt research involving human subjects

― Parental permission required for all research use of such specimens ― Waiver of consent prohibited

― The Act by its own terms is superseded by the Common Rule revisions ― Research involving newborn DBS will be treated like any other research involving biological specimens

24

Change to Definition of “In Writing” - Commentary

• Helpful clarification coming one month after joint FDA and OHRP guidance on the

use of electronic informed consent ― See FDA & OHRP , Use of Electronic Informed Consent, Questions & Answers: Guidance for Institutional Review Boards, Investigators and Sponsors (Dec. 2016)

• Refer to the e-consent guidance for distinctions between OHRP and FDA-regulated

research pertaining to: ― Electronic signature requirements

― FDA required Part 11 compliance

― Verification of subject identity

― FDA requires for all research ― OHRP takes a risk-based approach

25

Final Rule changes to exemptions for secondary use research: §__.104(d)(4)

• Exemptions for secondary use research of IPI or identifiable

biospecimens

• New .104(d)(4) [expanded from current Common Rule exemption

.101(b)(4)]: ― Publicly available; ― Information recorded by the investigator such that identity cannot readily be ascertained directly or through identifiers; investigator does not contact subjects; investigator will not re- identify subjects; OR ― Research involves only information collection and analysis regulated under HIPAA as ‘‘health care operations,’’ ‘‘research,’’

• r ‘‘public health activities and purposes’’

26

Final Rule new exemption for storage of identifiable private information or identifiable biospecimens for potential secondary use research: §__.104(d)(7)

• IRB conducts “limited IRB review” and makes the following

determinations: ― Broad consent for storage, maintenance, and secondary research use of IPI or identifiable biospecimens is obtained in accordance with .116(a)(1)–(4), (a)(6), and (d); ― Broad consent is appropriately documented or waiver of documentation is appropriate, in accordance with .117; AND ― If there is a change made for research purposes in the way the IPI

• r identifiable biospecimens are stored or maintained, there are

adequate provisions to protect the privacy of subjects and maintain confidentiality of data

27

Final Rule new exemption for secondary research use of identifiable information or identifiable biospecimens: §__.104(d)(8)

• Broad consent was obtained in accordance with .116(a)(1)-(4), (a)(6), and (d);
• Documentation of informed consent or waiver of documentation obtained in

accordance with .117;

• IRB conducts “limited IRB review” and makes the following determinations:

― when appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data (under .111(a)(7)), AND ― research to be conducted is within the scope of the broad consent obtained; AND

• Investigator does not include returning individual research results to subjects as

part of the study plan ― Note the caveat: “This provision does not prevent an investigator from abiding by any legal requirements to return individual research results.”

28

Final Rule new concept of limited IRB review

• Only available for purposes of new exemptions at

.104(d)(2)(iii), (d)(3)(i)(C), (d)(7) or (8)

• Only referenced IRB determinations are required
• Can be performed through expedited review (.110(b)(1)(iii))
• No continuing review required (.109(f)(1)(ii))
• If limited IRB review conducted by an external IRB, institution

and organization operating the IRB must document institution’s reliance on the IRB for oversight of the research and the responsibilities that each entity will undertake to ensure regulatory compliance (.103(e))

29

Exemptions for Secondary Research Use: No Consent Required - Commentary

• If identifiable private information or identifiable biospecimens are publicly available

― Broad interpretation of “publicly available” ― Includes government/institutional/library/commercial materials made available upon request, registration, or fee

• Information is recorded such that identity of subjects cannot readily be ascertained

― Difference from pre-2018 rule: extends to future, not only existing, collections

• f biospecimens/information

30

Exemptions for Secondary Research Use: No Consent Required (cont’d)- Commentary

• Research involves only information collection and analysis regulated by HIPAA

― HIPAA requirements on the use and disclosure of PHI for secondary research purposes, such as obtaining patient authorization (or IRB/privacy board waiver thereof), often apply concurrently with the requirements of the Common Rule ― This exemption is designed to minimize duplicative regulation by HIPAA and the Common Rule by providing that if the secondary research takes place at an institution subject to HIPAA (i.e., a “covered entity” or in certain cases a “business associate”) it will be exempt from the Common Rule ― HIPAA protections, such as authorization (or waiver) for future, secondary research uses of ― But privacy board review may be of more limited scope than IRB’s ― Exemption does not apply if information originates at a HIPAA-regulated entity and then is disclosed to an investigator who is not subject to HIPAA (e.g., a researcher at a non-covered entity) for use in research

31

Exemptions for Storage and Maintenance for Secondary Research Use: Broad Consent - Commentary

• In general, exempts storage, maintenance and secondary research use from full IRB

review, but does require limited IRB review, if broad consent is obtained and the proposed activity is within the scope of the broad consent

• Storage and maintenance for potential secondary research use

― IRB determines that broad consent is obtained and documented appropriately ― Open question regarding what degree of IRB diligence is required for these determinations? ― HHS-template described in NPRM has been dropped; institutions have flexibility to create own broad consent forms ― As part of limited IRB review, IRBs must determine that the broad consent form used contains the required elements and was appropriately documented

• r documentation waived

32

Exemptions for Secondary Research Use: Broad Consent - Commentary

• Secondary research use for which broad consent is required

― IRB determines there are adequate protections for privacy and confidentiality

― New criterion for IRB review and approval ― May not be experienced (await HHS guidance)

― Investigator cannot include returning individual research results to subjects as part of study plan (unless legally required to do so)

― May create a disincentive for returning individual research results ― Can return aggregate results ― Would returning incidental findings make the research ineligible for exemption? ― Preamble states that when secondary studies include a plan to return research results, appropriate for the study to be reviewed fully by an IRB to ensure that research results are returned to subjects in an appropriate manner

• If secondary research use is not eligible for exemption, broad consent is still

available but requires full IRB review

33

Final Rule Changes to Expedited Review: §__.110

• Expedited review list: §__.110(a)

― List evaluated at least every 8 years ― Consultation with other federal departments and agencies ― Published after notice and comment

• An IRB may use expedited review procedures when. . . .

― Research on expedited review list unless reviewer determines the study involves more than minimal risk (§__.110(b)(1)(i))

― shift in presumption: prior rule only allowed IRB to use expedited review procedures for research on expedited review list if reviewer finds research involves no more than minimal risk

34

Final Rule Changes to Expedited Review: §__.115(a)(8)

• An IRB may also use expedited review procedures when. . . .

― minor changes in approved research (§__.110(b)(1)(ii)) ― limited IRB review for certain exempt research (§__.110(b)(1)(iii))

• New documentation requirement: §__.115(a)(8)

― Adequate documentation of rationale for an expedited reviewer’s determination under §__.110(b)(1)(i) that research appearing on the expedited review list is more than minimal risk

35

Change to Expedited Review - Commentary

• Presumption that activities on the Secretary’s list of expedited-review-eligible

activities are minimal risk should ease administrative burden on IRBs by eliminating need to determine whether an event on the list is also minimal risk ― Assists potentially risk averse institutions in determining that research meets requirements for expedited review ― Frees up time at convened meetings of an IRB panel for review of higher risk research

• Clarification that expedited review process can be used for limited IRB review

required by certain exemption categories (e.g., the exemptions involving broad consent) will minimize administrative burden of such reviews

• Requirement that Secretary update the list of activities eligible for expedited

review at least once every eight years should provide opportunity for re-evaluation

• f the list in light of new technologies and types of research, and potentially more

frequent updates (current list dates from 1998)

• 36

Final Rule Changes to Continuing Review

• General rule on continuing review: §__.109(e)
• Continuing Review not required (unless IRB decides otherwise) if

(§__.109(f)(1)(i)-(iii)): ― Research eligible for expedited review; ― Research reviewed by an IRB through a limited IRB review; or ― Research progressed to the point that it only involves, as part of IRB- approved study, data analysis and/or accessing follow-up clinical data in certain circumstances

• New documentation requirement: §__.115(a)(3):

― Records of continuing review activities, including rationale for conducting continuing review of research that otherwise would not require continuing review

37

Streamlining of Continuing Review - Commentary

• Continues trend of reducing IRB review of activities that are unlikely to put

subjects at risk ― Many of the types of research that will be excluded from continuing review requirement (e.g., research that involves only data analysis) are under the pre-2018 rule eligible for expedited continuing review ― As with expedited review, attempts to minimize burden added to IRBs by the “limited review” required for certain exemption categories ― Did not finalize provision of the NPRM that would have required investigators to submit an annual confirmation to the IRB that the research is ongoing and that no changes have been made that would require the IRB to conduct continuing review

38

Final Rule New Mandated Single IRB Review: §.114(b)

• U.S. institution engaged in cooperative research must rely on a single IRB

approval for the portion of the research conducted in U.S. ― Cooperative research = research involving more than 1 institution

• The reviewing single IRB must be either:

― identified by Federal department or agency supporting or conducting the research, or ― proposed by lead institution , and subject to the acceptance of Federal department or agency supporting the research ― Final Rule preamble indicates consistency with NIH single IRB policy (published June 21, 2016)

39

Final Rule Exceptions to New Mandated Single IRB Review: §.114(b)

• Tw0 exceptions to Final Rule single IRB mandate:

― Research for which more than single IRB review is required by law (including tribal law passed by the official governing body of an American Indian or Alaska Native tribe); or ― Research for which any Federal department or agency supporting or conducting the research determines and documents that use of single IRB is not appropriate for the particular context *NIH sIRB policy also includes allowance for exceptions:

“Exceptions to this policy will be made where review by the proposed sIRB would be prohibited by a federal, tribal, or state law, regulation, or policy. Requests for exceptions that are not based on a legal, regulatory, or policy requirement will be considered if there is a compelling justification for the exception. The NIH will determine whether to grant an exception following an assessment of the need.”

40

Final Rule New Jurisdiction over Independent IRBs: §.101(a)

• “Institutions that are engaged in research described in this paragraph and

institutional review boards (IRBs) reviewing research that is subject to this policy must comply with this policy”(emphasis added)

• As stated in Final Rule preamble:

― Provides Common Rule departments and agencies authority to enforce compliance directly against IRBs not operated by FWA-holding institution ― Allows Common Rule departments and agencies to avoid involving other engaged institutions in enforcement activities related to the responsibilities of reviewing IRB ― Anticipated to reassure institutions using external IRB because compliance actions can be directed against the IRB responsible for regulatory noncompliance, rather than against the relying institution

41

Single IRB Review – Commentary

• Lead institution can propose the central IRB but federal department or agency must

approve

• Currently, many multisite research studies rely on a central IRB, though the extent of

activity and involvement of local IRBs varies ― Local IRBs may rely entirely on central IRB ― Local IRBs may conduct initial review and rely on central IRB for continuing reviews ― Local IRBs may condition reliance on receipt of adverse event information and progress reports ― Local IRBs may condition reliance on central IRB’s incorporation of community values, institutional policies

42

Single IRB Review – Commentary

• Central IRBs already common for drug trials; FDA formally recommended in 2006

― FDA had not recommended central IRBs for multisite device studies based on a statutory prohibition in FDA law ― However, the 21st Century Cures (December 2016) deleted the statutory bar to facilitate use

• Consistent with NIH expectation that research funded by NIH use a single IRB of record
• Intended to reduce administrative duplication, cost, time, and burdens
• Some commenters opposed the mandate and advocated for an optional policy
• Local IRBs may continue to provide input during IRB review phase, but central IRB is not

required to adopt; options for local institutions: ― Attempt to force central IRBs to accept input through authorization agreement; or ― Drop out or refuse to be in study if sufficiently egregious

• Responsibility of central IRB membership under §.107 to know (i) laws applicable to each
• f the sites and (ii) relevant “community attitudes”

43

Jurisdiction over Independent IRBs – Commentary

• Previously when an institution relied on an IRB that it did not itself operate, OHRP

would hold accountable the institution for any IRB noncompliance

• Now Common Rule departments and agencies are authorized to enforce compliance

directly against independent IRBs

• Should ease liability concerns of institutions using independent IRBs because the

government can take compliance action directly against the IRB responsible for the regulatory violation, rather than against the institution that relied on the IRB’s review

• May increase the use of central IRBs in multi-site research by eliminating one of the

major concerns that institutions have had regarding central IRB reliance

44

Final Rule Revisions to Study-Specific Informed Consent: §§.116(a)(5), .116(b)(9)

• Begin with key information most likely to assist subject/LAR in understanding why
• r why not to participate; organized and presented to facilitate comprehension

(.116(a)(5)(i)) (does not apply to broad consent)

• Overall, must present information in sufficient detail, organization, and

presentation to facilitate subject/LAR understanding of why or why not participate (116(a)(5)(ii)) (does not apply to broad consent)

• Must include either statement:

― Identifiers might be removed from IPI or identifiable biospecimens and stripped information or biospecimens could be used for future research studies or given to another investigator for future research studies without additional informed consent; OR ― Subject’s information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies (.116(b)(9))

45

Final Rule Revisions to Study-Specific Informed Consent: §§.116(c)(7)-(9)

• When appropriate, informed consent must include the following

statements:

• The subject’s biospecimens (even if identifiers are removed) may be

used for commercial profit and whether the subject will or will not share in this commercial profit (.116(c)(7))

• Whether clinically relevant research results will be disclosed to

subjects, and if so, under what conditions (.116(c)(8))

• For research involving biospecimens, whether the research will (if

known) or might include whole genome sequencing (.116(c)(9))

46

Changes to Informed Consent Process - Commentary

• Attempt to address the growing length, complexity, and contractual nature of

consent forms

• Intended to facilitate shorter and more understandable consent language
• New requirement that prospective subject “be provided with the information that

a reasonable person would want to have in order to make an informed decision about whether to participate” ― Unclear when information beyond the basic and additional elements would be required, and under what circumstances ― Should be a presumption that required elements satisfy the reasonableness standard ― Could invite subjects to argue in a negligence case that they were not provided with all information that a reasonable person would expect

• In general, consent forms should be reorganized and should more actively promote

understandability of the salient aspects of the research

• Sequence of information now will be more closely scrutinized

47

New Basic Element of Consent - Commentary

• Option: “Subject’s information or biospecimens collected as part of the research,

even if identifiers are removed, will not be used or distributed for future research studies” ― Investigators generally will not select because voluntarily hamstrings institutions and researchers from de-identifying data and biospecimens and using for future research purposes ― In fact, the NPRM preamble states that it is anticipated that very few investigators will elect to offer the option to restrict the future research use

• f non-identified data, in part because of the challenges of marking and

tracking such decisions ― However, if this option is offered, institutions and investigators must develop a system for tracking impermissible uses of non-identified information ― The prohibition does not extend to nonresearch uses of the leftover data and biospecimens, such as for education, training, quality improvement, and quality assurance

48

New Additional Elements of Consent- Commentary

• “Subject’s biospecimens may be used for commercial profit and whether the

subject will or will not share in this commercial profit” ― Already in many consent forms ― Unlikely for institution and investigator to profit share with subjects

• ‘‘For research involving biospecimens, whether the research will (if known) or

might include whole genome sequencing (i.e., sequencing of a human germline or somatic specimen with the intent to generate the genome or exome sequence of that specimen)”

• Not proposed in NPRM
• Added because of unique implications of the information that can be developed

through whole genome sequencing, such as important insights into the health of individuals as well as their biological families

49

Final Rule New Allowance for Broad Informed Consent: §.116(d)

• New regulatory allowance for broad consent for storage,

maintenance, and secondary research use of IPI or identifiable biospecimens

• A regulatory flexibility, not an independent requirement (although
• perates as a condition of exemptions .104(d)(7) and (8))
• Thus, no “waiver” of broad consent – just waiver of consent
• From the Final Rule preamble, alternatives to broad consent:

― Study specific informed consent in accordance with .116(a), (b), (c) ― Waiver of informed consent under .116(e) or (f) ― Exemption under .104(d)(4), (7), or (8)

50

Final Rule Elements of Broad Informed Consent: §.116(d) (continued)

• Study-specific elements .116(b)(2), (3),(5), (8); if appropriate (c)(7) and (9); + 6 new
• New elements, describing or stating:

― General types of research that may be conducted, such that “reasonable person” would expect that broad consent permits the research ― IPI or identifiable biospecimens covered, whether IPI or identifiable biospecimens might be shared, the types of using institutions or researchers ― Period of time stored and maintained, period of time that the IPI or identifiable biospecimens may be used (both could be indefinite) ― Subject/LAR will not be given details of studies and they might have chosen not to consent to some of those specific research studies (unless they will be so informed) ― Clinically relevant research results may not be disclosed to the subject (unless it is known they always will be provided) ― Whom to ask about subject’s rights, storage and use of subject’s IPI or identifiable biospecimens, and whom to contact in the event of research-related harm

51

Broad Consent Elements - Commentary

• Primary differences between broad and study specific consent, broad consent:

― Not required to begin with concise and focused presentation of key information ― Not required to be organized in a manner that facilitates understanding instead of listing isolated facts ― Not required to disclose specific procedures that will be followed ― Not required to disclose appropriate alternatives

• Option to obtain broad consent for future use of identifiable biospecimens and

identifiable private information provides a new alternative for investigators ― In addition to the options available under the pre-2018 rule: (i) obtaining an IRB waiver of consent or (ii) obtaining study-specific consent for each protocol

52

Broad Consent Elements (cont’d) - Commentary

• Regarding timeframe, if institutions self-impose a timeframe for storage, maintenance, and

secondary research use, those data and biospecimens must be tracked and discontinued after the timeframe expires (unless additional consent is obtained) ― No incentive for voluntarily binding an institution to a definite timeframe ― Institutions will be motivated to store, maintain and conduct secondary research indefinitely

• Broad consent must contain the same basic element as study-specific consent related to the

voluntariness of enrolling and withdrawing from the study, at any time ― However, information that has been stripped of identifiers might not be traceable and thus might not be feasible to withdraw consent for future use or distribution ― If investigator commits to permitting a subject to discontinue use of subject’s identifiable private information or identifiable biospecimens, investigator is expected to honor this commitment and not remove identifiers ― Thus, investigators would be incentivized to inform the subject that his/her biospecimens and information will be deidentified, and, once the identifiers are stripped, the further distribution or research use could not be discontinued based on inability to trace

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Final Rule Revisions to Waiver or Alteration of Informed Consent Criteria: §.116(f)(1)-(3)

• New waiver limitation (.116(f)(1)): if individual was asked to provide broad

consent, and refused to consent, IRB cannot waive consent for storage, maintenance, or secondary research use of IPI or identifiable biospecimens

• New alteration limitations (.116(f)(2)):

― Explicit statement that IRB may not omit or alter any of the requirements at .116(a) ― If a broad consent procedure is used, an IRB may not omit or alter any of the required elements of broad consent

• New waiver/alteration criterion (.116(f)(3)):

― If research will use IPI or identifiable biospecimens, research could not practicably be carried out without using such information or biospecimens in an identifiable format

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Waiver of Consent - Commentary

• Criterion – research could not practicably be carried out without accessing or using identifiers

― Similar criterion in HIPAA Privacy Rule’s requirements for a waiver of HIPAA authorization, which requires that the research could not practicably be conducted without access to and use of the PHI ― ‘‘Nonidentified information should be used whenever possible in order to respect subjects’ interests in protecting the confidentiality of their data and biospecimens’’ (preamble) ― Will require that investigators accurately predict whether proposed biospecimen research will require identifiers at any point during the conduct of the study ― Researchers will be encouraged to use de-identified biospecimens for proposed research to be eligible for waiver ― Incentive structure will push more research to use de-identified information and biospecimens based on the likelihood of obtaining a waiver could not meet the new criterion, even if using identifiable data may be more scientifically compelling ― IRBs will be asked to make determinations regarding whether a proposed biospecimen study requires the use of identifiers, which may be beyond the current expertise and qualifications of many IRB members.

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Waiver of Consent (cont’d) - Commentary

• Criterion: If an individual was asked to provide broad consent and “refused,” IRB cannot waive

for storage, maintenance or secondary research use of identifiable biospecimens/information ― What constitutes “refusal” – silence (failure to respond) or express declination on the consent form (or orally) ― Institutions will be forced to track refusals and associated biospecimens and information ― Scope of refusal

― Will it bar research team, entire institution, or all researchers? Depends on how the scope

• f the broad consent is written

― Would not prevent recontacting the individual ― Would not prevent from requesting an additional broad consent for a different scope than what was initially requested (e.g., if initial broad consent were limited to diabetes research conducted at X hospital and subject refused, may still be able to request broad consent for heart disease research at Y hospital)

― Under strict reading, researchers

― May still de-identify and use the data; or ― Pursue an exemption

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Final Rule New Exception to Informed Consent for Screening or Recruiting Subjects: §.116(g)

• IRB may approve research in which an investigator will obtain information or

biospecimens for screening, recruiting, or determining the eligibility of prospective subjects, without informed consent, if: ― Investigator will obtain information through oral or written communication with the prospective subject or legally authorized representative, OR ― Investigator will obtain IPI or identifiable biospecimens by accessing records

• r stored biospecimens
• From the Final Rule preamble:

― Harmonizes with FDA expectations ― Information collection activities are reviewed by the IRB as part of the research, so IRB must make .111 determinations, including that privacy and confidentiality protections are adequate for information obtained

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Final Rule Public Posting of Consent Forms: §.116(h)

• For clinical trial conducted or supported by a Common Rule department or

agency: ― One IRB approved consent form must be posted by the awardee or the Federal department or agency component conducting the trial ― On to-be-established publicly available Federal website

• If conducting or supporting Common Rule agency determines certain

information should not be made publicly available, redactions can be permitted or required

• Consent form must be posted

― After clinical trial is closed to recruitment, AND ― no later than 60 days after the last study visit by any subject required by the protocol

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Screening/Recruiting Exception to Informed Consent - Commentary

• Takes a step toward harmonizing Common Rule approach to these activities with

that of the FDA’s human subjects regulations and HIPAA ― FDA guidance on informed consent states that preliminary review of a patient’s record and recording of limited information to determine eligibility is not itself a “clinical investigation” ― HIPAA has long permitted a review “preparatory to research” without subject authorization or waiver thereof provided that no PHI leaves the covered entity

― 21st Century Cures Act requires clarification on scope of this provision

• Final rule preamble makes clear that the IRB must review and approve the entire

research proposal before approving this exception ― Potentially differs from FDA and HIPAA requirements on this point

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Public Posting of Consent Forms from Clinical Trials – Commentary

• Final rule preamble states that most commenters opposed this proposal

― Concern that this requirement may increase length of consent forms, thus running counter to the final rule’s goal of simplifying consent forms ― Proprietary information may be redacted only if the federal department/agency funding the research determines that redaction is necessary

• Flexibility of posting only one version of the consent form is a helpful change from

the proposed rule

• Clarification will be needed regarding which website will be used for the posting;

possibility of using ClinicalTrials.gov may ease administrative burden

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Revised Common Rule & FDA Regulations – Commentary

• FDA human subjects protections regulations apply to clinical investigations of medical

products (drugs, devices, biological products) to assess safety or effectiveness, regardless

• f funding source
• Recent activity indicates strong desire to harmonize Common Rule and FDA requirements

― Recent 21st Century Cures Act requires HHS Secretary, to the extent practicable and consistent with other statutory authorities, to harmonize the differences between the Common Rule and FDA’s human subject regulations within 3 years ― Final Rule preamble states intent is to update FDA regulations

• Likely that FDA and OHRP will continue to collaborate and jointly issue human subjects

protections guidance documents, to the extent consistent with statute and agency mission

• 21s Century Cures Act eliminated two prior statutory impediments to harmonization

― Deletion of requirement that multisite FDA-regulated device studies be reviewed by a local IRB; and ― Addition of an informed consent waiver for minimal risk research (not self-executing, requires FDA to promulgate regulations establishing appropriate safeguards)

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Thank You

David Peloquin Ropes & Gray LLP david.peloquin@ropesgray.com 617.951.7786 Abram Barth Ropes & Gray LLP abram.barth@ropesgray.com 212.596.9040 Emily Levine Senior Attorney Office of General Counsel HHS Laura Odwazny Senior Attorney Office of General Counsel HHS

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