Subpart A Subcommittee(SAS)

Subpart A Subcommittee(SAS)

Elizabeth Bankert and Daniel NelsonElizabeth Bankert and Daniel NelsonSAS Co-ChairsSAS Co-Chairs

with David Borasky, SAS Memberwith David Borasky, SAS Member

Presentation to the Secretary’s Advisory Committee on Human Research Protections

(SACHRP)October 19, 2010

Outline of Today’s PresentationOutline of Today’s Presentation

• Subcommittee charge and membership

• Topic for consideration at this meeting

• Biospecimen FAQs one loose end

• Update on ongoing work • Informed consent Form & Process

Charge to the Subcommittee Charge to the Subcommittee

• Review and assess • All provisions of Subpart A of 45 CFR 46• Relevant OHRP guidance documents

• Based on this review and assessment• Develop recommendations for consideration by

SACHRP in three categories:• Interpretation of specific Subpart A provisions• Development of new or modification of existing OHRP

guidance• Possible revisions to Subpart A

Based on memo to Subcommittee from E. Prentice, Chair of SACHRP, 1/14/05and subsequent discussion by SACHRP

Charge to the Subcommittee Charge to the Subcommittee

• Goals • Enhance protection of human subjects • Reduce regulatory burdens that do not

contribute to the protection of human subjects

• Promote scientifically and ethically valid researchh

Based on memo to Subcommittee from E. Prentice, Chair of SACHRP, 1/14/05and subsequent discussion by SACHRP

Subpart A SubcommitteePresent Members

Subpart A SubcommitteePresent Members

• Elizabeth Bankert,* Dartmouth College• Laura Beskow, Duke University• David Borasky, RTI International• Bruce Gordon, University of Nebraska Medical Center • Susan Kornetsky, Children’s Hospital Boston• Gigi McMillan, We Can Pediatric Brain Tumor Network• Daniel Nelson,* University of North Carolina - Chapel Hill• Susan Rose, University of Southern California• Michele Russell-Einhorn, Dana Farber Cancer Institute• Ada Sue Selwitz, University of Kentucky

• With welcome input from • SACHRP members who choose to affiliate• Ex officio reps of Common Rule agencies

*co-chairs

Subpart A SubcommitteePast Members

Subpart A SubcommitteePast Members

• Ricky Bluthenthal, RAND Corporation• Gary Chadwick, University of Rochester• Felix Gyi, Chesapeake Research Review, Inc• Isaac Hopkins, Community Research Advocate (UMDNJ) †• Nancy Jones, Wake Forest University NIH• Moira Keane, University of Minnesota• Ernest Prentice, University of Nebraska Medical Center• Thomas Puglisi, PriceWaterhouse Coopers VA• Lorna Rhodes, University of Washington• David Strauss, New York State Psychiatric Institute

• Not shown are multiple SACHRP members who chose to affiliate with SAS while members of parent committee

Subcommittee MeetingsSubcommittee Meetings

• January 18, 2005 via teleconference January 18, 2005 via teleconference

• February 14, 2005 in Alexandria, VAFebruary 14, 2005 in Alexandria, VA

• May 20, 2005 via teleconferenceMay 20, 2005 via teleconference

• July 20-21, 2005 in Alexandria, VAJuly 20-21, 2005 in Alexandria, VA

• October 4, 2005 via teleconferenceOctober 4, 2005 via teleconference

• January 9, 2006 via teleconferenceJanuary 9, 2006 via teleconference

• January 30-31, 2006 in Rockville, MDJanuary 30-31, 2006 in Rockville, MD

• May 11-12, 2006 in Gaithersburg, MDMay 11-12, 2006 in Gaithersburg, MD

• September 11, 2006 via teleconferenceSeptember 11, 2006 via teleconference

• October 4, 2006 via teleconferenceOctober 4, 2006 via teleconference

• February 15-16, 2007 in Arlington, VA (with February 15-16, 2007 in Arlington, VA (with retreat)retreat)

• March 9, 2007 via teleconferenceMarch 9, 2007 via teleconference

• May 31-June 1, 2007 in Arlington, VA May 31-June 1, 2007 in Arlington, VA

• July 16, 2007 via teleconferenceJuly 16, 2007 via teleconference

• August 16-17, 2007 in Arlington, VAAugust 16-17, 2007 in Arlington, VA

• October 3, 2007 via teleconferenceOctober 3, 2007 via teleconference

• February 21, 2008 in Rockville, MDFebruary 21, 2008 in Rockville, MD

• May 15-16, 2008 in Rockville, MDMay 15-16, 2008 in Rockville, MD

• September 22-23, 2008 in Rockville, MDSeptember 22-23, 2008 in Rockville, MD

• January 26-27, 2009 in Rockville, MDJanuary 26-27, 2009 in Rockville, MD

• June 8 & 30, 2009 via teleconferenceJune 8 & 30, 2009 via teleconference

• July 8, 2009 via teleconferenceJuly 8, 2009 via teleconference

• Sept 1 & 30, 2009 via teleconferenceSept 1 & 30, 2009 via teleconference

• Oct 21, 2009 via teleconferenceOct 21, 2009 via teleconference

• Feb 24 & 26, 2010 via teleconferenceFeb 24 & 26, 2010 via teleconference

• Jun 1-2, 2010 in Rockville, MDJun 1-2, 2010 in Rockville, MD

• Jun 30, 2010 via teleconferenceJun 30, 2010 via teleconference

• Sept 27, 2010 via teleconferenceSept 27, 2010 via teleconference

Supplemented by Working Group calls and e-mailsSupplemented by Working Group calls and e-mails

Secretarial Letters Incorporating SAS RecommendationsSecretarial Letters Incorporating SAS Recommendations

• 5th SACHRP letter to Secretary Leavitt 3/14/07• Recommendations approved 2005-2006

• Continuing Review Federal Register notice on 11/06/09• Expedited Review Federal Register notice on 10/26/07

• 6th SACHRP letter to Secretary Leavitt 6/15/07• Recommendations approved March 2007

• Required Training Federal Register notice on 07/01/08 • 7th SACHRP letter to Secretary Leavitt 1/31/08

• Recommendations approved March & July 2007• Waiver of Informed Consent• Minimal Risk Analytical framework and examples

• 8th SACHRP letter to Secretary Leavitt 9/18/08• Recommendations approved Oct 2007, March & July 2008

• Exemptions• Alternative models of IRB review• IRB membership rosters• Waiver of documentation of informed consent• Institutional Officials• American Indians and Alaska Natives• (Letter also addressed disaster research, and systems-level commentary)

• 10th SACHRP letter to Secretary Sebelius 7/15/09• Recommendations approved March 2009

• Designation of IRBs within FWA• 11th SACHRP letter to Secretary Sebelius 3/24/10

• Reaffirmation of previous rec on required education, after public RFI

Questions Relating to Informed Consent and

Research Use of Biospecimens

Questions Relating to Informed Consent and

Research Use of Biospecimens

Subpart A Subcommittee (SAS) Report and Recommendations to SACHRP

Biospecimen FAQsBiospecimen FAQs

Over the course of several SACHRP meetings, the full set of FAQs on this topic (#1- 28) have been presented and approved, modified or deleted. While these recommendations have yet to be finalized via Secretarial letter, one issue has already arisen with regard to the formatting of a single FAQ. This issue only is being revisited today, for the sake of clarification.

Background on FAQ #3Background on FAQ #3

• FAQ #3 described a scenario where researchers proposed to use FAQ #3 described a scenario where researchers proposed to use specimens for a purpose that was not compatible with the original specimens for a purpose that was not compatible with the original consent. This was a particularly controversial scenario, which consent. This was a particularly controversial scenario, which received much discussion. received much discussion.

• At the SACHRP meeting on October 27, 2009, the majority of the At the SACHRP meeting on October 27, 2009, the majority of the response (the first 2 of 3 bullets) was approved, but the 3response (the first 2 of 3 bullets) was approved, but the 3 rdrd bullet bullet was returned for further consideration on the following day, after a was returned for further consideration on the following day, after a SACHRP member offered to rework that part of the response.SACHRP member offered to rework that part of the response.

• On October 28, 2009, the 3On October 28, 2009, the 3rdrd bullet was reintroduced, discussed bullet was reintroduced, discussed and approved.and approved.

Background on FAQ #3(continued)

Background on FAQ #3(continued)

• Despite being considered as “a separate recommendation” (per the minutes), the 3rd bullet did not truly stand alone, based as it was on the identical scenario described in FAQ #3. Nevertheless, when documented in the archival compilation of all FAQs, the original scenario was repeated as FAQ #3 and FAQ #3A.

• Because the scenarios in FAQ #3 and FAQ #3A are identical, this is Because the scenarios in FAQ #3 and FAQ #3A are identical, this is already leading to confusion among readers, and even among some already leading to confusion among readers, and even among some SACHRP members who are familiar with this background. The SACHRP members who are familiar with this background. The separation of the two answers is, to a large extent, an artifact of the way separation of the two answers is, to a large extent, an artifact of the way this scenario was resolved on two separate days.  In reality, the this scenario was resolved on two separate days.  In reality, the answers are parts of a whole and do not entirely make sense when answers are parts of a whole and do not entirely make sense when viewed on their own.  viewed on their own. 

FAQ #3 (as revised and approved)

FAQ #3 (as revised and approved)

• Blood samples were obtained for research purposes, with Blood samples were obtained for research purposes, with informed consent of the subjects, and the original study has informed consent of the subjects, and the original study has been completed. The samples remain under the control of been completed. The samples remain under the control of the original investigator. Another investigator wants to use the original investigator. Another investigator wants to use a portion of the remaining samples to perform research a portion of the remaining samples to perform research completely unrelated to the original study. completely unrelated to the original study.

• If the original consent stated that “…your sample will only If the original consent stated that “…your sample will only be used for research on colon cancer,” but the secondary be used for research on colon cancer,” but the secondary user is interested in studying Alzheimer’s disease, can the user is interested in studying Alzheimer’s disease, can the samples still be used if provided to the secondary user in a samples still be used if provided to the secondary user in a coded fashion?coded fashion?

FAQ #3 RESPONSE(as revised and approved)

FAQ #3 RESPONSE(as revised and approved)

• The secondary use of de-identified or coded samples is not research The secondary use of de-identified or coded samples is not research involving human subjects under 45 CFR 46. Nevertheless, the involving human subjects under 45 CFR 46. Nevertheless, the original investigator and his/her institution have made an agreement original investigator and his/her institution have made an agreement with the subjects about use of their specimens, and have an with the subjects about use of their specimens, and have an obligation to honor that agreement. obligation to honor that agreement.

• Institutions should establish mechanisms to determine whether Institutions should establish mechanisms to determine whether secondary uses are compatible with the original informed consent; secondary uses are compatible with the original informed consent; this could involve consultation with the IRB that approved the original this could involve consultation with the IRB that approved the original research, or review by some other body designated for these research, or review by some other body designated for these purposes. Coding should not be used as a means to circumvent the purposes. Coding should not be used as a means to circumvent the original terms of consent. This is ethically problematic, even if the original terms of consent. This is ethically problematic, even if the original project is over and the secondary use is no longer considered original project is over and the secondary use is no longer considered to be research involving human subjects.to be research involving human subjects.

FAQ #3 COMBINED RESPONSE(REVISED ON 10-19-2010)

FAQ #3 COMBINED RESPONSE(REVISED ON 10-19-2010)

• The secondary use of de-identified or coded samples is not research involving The secondary use of de-identified or coded samples is not research involving human subjects under 45 CFR 46. In the case where secondary use of tissue human subjects under 45 CFR 46. In the case where secondary use of tissue samples is not compatible with the original consent for tissues that are de-samples is not compatible with the original consent for tissues that are de-identified, coded, or anonymized and are not readily identifiable, the samples identified, coded, or anonymized and are not readily identifiable, the samples are no longer subject to human subject regulations. Thus, there is no regulatory are no longer subject to human subject regulations. Thus, there is no regulatory violation.violation. Nevertheless, the original investigator and his/her institution have Nevertheless, the original investigator and his/her institution have made an agreement with the subjects about use of their specimens, and have made an agreement with the subjects about use of their specimens, and have an obligation to honor that agreement. an obligation to honor that agreement.

• Institutions should establish mechanisms to determine whether secondary uses Institutions should establish mechanisms to determine whether secondary uses are compatible with the original informed consent; this could involve are compatible with the original informed consent; this could involve consultation with the IRB that approved the original research, or review by some consultation with the IRB that approved the original research, or review by some other body designated for these purposes. Coding should not be used as a other body designated for these purposes. Coding should not be used as a means to circumvent the original terms of consent. This is ethically problematic, means to circumvent the original terms of consent. This is ethically problematic, even if the original project is over and the secondary use is no longer even if the original project is over and the secondary use is no longer considered to be research involving human subjects.considered to be research involving human subjects.

FAQ #3A (NOTE: Identical to FAQ #3)

FAQ #3A (NOTE: Identical to FAQ #3)

• Blood samples were obtained for research purposes, with Blood samples were obtained for research purposes, with informed consent of the subjects, and the original study has informed consent of the subjects, and the original study has been completed. The samples remain under the control of been completed. The samples remain under the control of the original investigator. Another investigator wants to use the original investigator. Another investigator wants to use a portion of the remaining samples to perform research a portion of the remaining samples to perform research completely unrelated to the original study. completely unrelated to the original study.

• If the original consent stated that “…your sample will only If the original consent stated that “…your sample will only be used for research on colon cancer,” but the secondary be used for research on colon cancer,” but the secondary user is interested in studying Alzheimer’s disease, can the user is interested in studying Alzheimer’s disease, can the samples still be used if provided to the secondary user in a samples still be used if provided to the secondary user in a coded fashion?coded fashion?

FAQ #3A RESPONSE(as revised and approved)

FAQ #3A RESPONSE(as revised and approved)

• In the case where secondary use of tissue samples is not In the case where secondary use of tissue samples is not compatible with the original consent for tissues that are compatible with the original consent for tissues that are de-identified, coded, or anonymized and are not readily de-identified, coded, or anonymized and are not readily identifiable, the samples are no longer subject to human identifiable, the samples are no longer subject to human subject regulations. Thus, there is no regulatory violation.subject regulations. Thus, there is no regulatory violation.

• MERGED WITH FIRST RESPONSE

RECOMMENDATIONRECOMMENDATION

Regarding the “packaging” of FAQ #3: Regarding the “packaging” of FAQ #3: • In order to minimize confusion by future In order to minimize confusion by future

readers of the SACHRP FAQs on research readers of the SACHRP FAQs on research use of biospecimens, it is proposed that the use of biospecimens, it is proposed that the scenarios currently labeled and presented scenarios currently labeled and presented individually as FAQ #3 and FAQ #3A be individually as FAQ #3 and FAQ #3A be recombined into a single FAQ, with a multi-part recombined into a single FAQ, with a multi-part response.response.

SAS WORK IN PROGRESS:

Improving the Form and Process of Informed

Consent

SAS WORK IN PROGRESS:

Improving the Form and Process of Informed

Consent

Problem StatementProblem Statement

The goal of the informed consent process is to The goal of the informed consent process is to ensure an individual’s voluntary informed ensure an individual’s voluntary informed decision to participate in research. Although the decision to participate in research. Although the regulations that govern informed consent are regulations that govern informed consent are designed to promote flexibility and the basic and designed to promote flexibility and the basic and additional elements of consent have remained additional elements of consent have remained unchanged, the level of detail provided in unchanged, the level of detail provided in consent forms has grown steadily since the consent forms has grown steadily since the regulations were enacted. regulations were enacted.

Problem Statement (2)Problem Statement (2)

Current approaches to consent forms and Current approaches to consent forms and processes are falling short of the goal of promoting processes are falling short of the goal of promoting voluntary decision making based on adequate voluntary decision making based on adequate understanding. Anecdotal and empirical evidence understanding. Anecdotal and empirical evidence indicates that potential participants may fail to indicates that potential participants may fail to understand critical aspects of the research, and understand critical aspects of the research, and that an overemphasis on the inclusion of detail has that an overemphasis on the inclusion of detail has led to lengthy and complex documents, a lack of led to lengthy and complex documents, a lack of attention to process, and problems with attention to process, and problems with comprehension.comprehension.

Problem Statement (3)Problem Statement (3)

Factors that contribute to the problem include:Factors that contribute to the problem include:• IRB review of consent documents that is increasingly focused IRB review of consent documents that is increasingly focused

on editorial review rather than a more meaningful review of on editorial review rather than a more meaningful review of the process by which consent will be obtained; the process by which consent will be obtained;

• Form has become the catch-all vehicle for related information Form has become the catch-all vehicle for related information that may not be central to the decision to participate (e.g., that may not be central to the decision to participate (e.g., HIPAA; GINA; protocol registries; sponsor and institutional HIPAA; GINA; protocol registries; sponsor and institutional liability concerns);liability concerns);

• Over-interpretation of regulatory requirements combined with Over-interpretation of regulatory requirements combined with a fear of omitting important information;a fear of omitting important information;

• Current education on human subjects protections typically Current education on human subjects protections typically stops short of training investigators and their staff on how to stops short of training investigators and their staff on how to promote and implement an effective informed consent promote and implement an effective informed consent process.process.

SAS Work to DateSAS Work to DateReview discussions about informed consent in Review discussions about informed consent in federal register documents federal register documents no big surprises no big surprises

•IC form is only a part of the larger processIC form is only a part of the larger process• ““The consent form, thus, should not be viewed as an The consent form, thus, should not be viewed as an

end point.”end point.”• ““The ‘form’ itself cannot substitute for the The ‘form’ itself cannot substitute for the

communicative process that it represents….”communicative process that it represents….”

•Language should be “understandable”Language should be “understandable”• ““The agency already requires consent documents to The agency already requires consent documents to

describe, in language that is understandable to describe, in language that is understandable to subjects, all relevant information about the study.”subjects, all relevant information about the study.”

SAS Work to Date (2)SAS Work to Date (2)

Review the current informed consent regulations Review the current informed consent regulations (45 CFR 116 & 117)(45 CFR 116 & 117)

•Are the regulations clear and do they IRBs with Are the regulations clear and do they IRBs with provide sufficient flexibility?provide sufficient flexibility?

• 46.116(a)(4) – appropriate alternative procedures or 46.116(a)(4) – appropriate alternative procedures or courses of treatment: When the only alternative is not courses of treatment: When the only alternative is not to participate? Off-label use?to participate? Off-label use?

• 46.116(a)(6) – research-related injury: Applicability to 46.116(a)(6) – research-related injury: Applicability to non-physical risks, i.e., when the main risk is to non-physical risks, i.e., when the main risk is to privacy/confidentiality, is this section supposed to privacy/confidentiality, is this section supposed to apply somehow? apply somehow? 

SAS Work to Date (3)SAS Work to Date (3)Review the current informed consent regulations Review the current informed consent regulations (45 CFR 116 & 117)(45 CFR 116 & 117)

•46.116(b) – optional elements: Not immediately clear 46.116(b) – optional elements: Not immediately clear when inclusion of these elements would be appropriate and when inclusion of these elements would be appropriate and when not appropriate.when not appropriate.

•46.116(d)(3) – waiver/alteration: The “could not practicably 46.116(d)(3) – waiver/alteration: The “could not practicably be carried out” criterion is not commonly understood Many be carried out” criterion is not commonly understood Many IRBs default to leaving unnecessary information in the form IRBs default to leaving unnecessary information in the form because difficult to argue that the research “could not because difficult to argue that the research “could not practicably be carried out” without the waiver or alteration. practicably be carried out” without the waiver or alteration. 

SAS Work to Date (4)SAS Work to Date (4)

Identify words/phrases in the regs that might Identify words/phrases in the regs that might require clarification, guidance, etc?require clarification, guidance, etc?

•““Language understandable to the subject”Language understandable to the subject”• Is this about translations or need to describe things in Is this about translations or need to describe things in

non-technical terms?non-technical terms?

•““legally effective”legally effective”• Does this mean that the IC form is a contract? What Does this mean that the IC form is a contract? What

is the legal status of IC?is the legal status of IC?

SAS Work to Date (5)SAS Work to Date (5)

Review of existing OHRP guidance on Informed Review of existing OHRP guidance on Informed ConsentConsent•Emergency Research (‘96)Emergency Research (‘96)•Exculpatory Language (‘96)Exculpatory Language (‘96)•Informed Consent Tips (‘93) Informed Consent Tips (‘93) •Informed Consent Checklist (‘98)Informed Consent Checklist (‘98)•Informed Consent, Legally Effective and Prospectively Informed Consent, Legally Effective and Prospectively Obtained (‘93)Obtained (‘93)•Informed Consent, Non-English Speakers (’95)Informed Consent, Non-English Speakers (’95)•Informed Consent Requirements for In Vitro Medical Device Informed Consent Requirements for In Vitro Medical Device Clinical Investigations Conducted Under FDA’s Interim Final Clinical Investigations Conducted Under FDA’s Interim Final Rule at 21 CFR 50.23(e) (‘06)Rule at 21 CFR 50.23(e) (‘06)

Review of existing OHRP Informed Consent FAQsReview of existing OHRP Informed Consent FAQs

SAS Work to Date (6)SAS Work to Date (6)

Conclusions from review of guidance and FAQsConclusions from review of guidance and FAQs

•Generally clear, well-writtenGenerally clear, well-written•Many answer the questions by quoting the regulationsMany answer the questions by quoting the regulations•Others provide useful model language (e.g., exculpatory Others provide useful model language (e.g., exculpatory language)language)•Some guidance documents appear quite dated (e.g., Some guidance documents appear quite dated (e.g., OPRR, MPAs)OPRR, MPAs)•May be a need for additional guidance or FAQs on May be a need for additional guidance or FAQs on issues/topics identified by SASissues/topics identified by SAS

SAS To-Do ListSAS To-Do List

• Review FDA guidance (e.g., information sheets; Review FDA guidance (e.g., information sheets; supervisory responsibilities)supervisory responsibilities)

• Identify common misperceptions that impact Identify common misperceptions that impact consent form and processconsent form and process• Catalog extra-regulatory information that ends up in Catalog extra-regulatory information that ends up in

informed consent documentsinformed consent documents• Misinterpretations that become “requirements” by IRBsMisinterpretations that become “requirements” by IRBs

• Toolkit repository for information and materials Toolkit repository for information and materials that were developed to improve the consent form that were developed to improve the consent form and processand process

SAS Next StepsSAS Next Steps• Complete the To-Do listComplete the To-Do list

• Develop recommendations for SACHRP Develop recommendations for SACHRP consideration. Under consideration:consideration. Under consideration:• Convene stakeholders’ meeting on ICConvene stakeholders’ meeting on IC• Training requirement for research staff who obtain ICTraining requirement for research staff who obtain IC• Additional guidance/FAQs on IC topicsAdditional guidance/FAQs on IC topics• Develop model language / form based on required Develop model language / form based on required

elements elements re-order to emphasize what is most re-order to emphasize what is most important; make the form conducive to good processimportant; make the form conducive to good process

• Identify and promote best practices for processIdentify and promote best practices for process

Stay tuned... there is always more to come from SAS!

Stay tuned... there is always more to come from SAS!