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Using Electronic Consent and Technologies in Research: Regulatory and IRB Considerations
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About Quorum Review IRB
Accredited Fully Accredited by the Association for Accreditation of Human
Research ProtectionPrograms (AAHRPP) through 2014 Fully compliant with FDA and OHRP requirements
International Boards available for the review of US and Canadian Studies
Strong Framework Approx. 180 employees – one of the largest IRBs in the US
Certified IRB Professionals (CIP) 60% of Affiliated IRB members, 40% of Regulatory staff
and 20% of study management & study support positions
The Quorum Advantage
8 Board meetings each week 24-hour site turnaround,
36-hour amendment review, and same day site changes
One time CV and audit documentation submission
Support available 8am-8pm ET Dedicated Study Manager
The Quorum Advantage
Secure portal with Smart Forms, status reports, and approval documents
Customized Phase I and Post-Marketing processes
Flexible, customized process for AMCs
100% Quality Control on all documents
About the Presenter
Regulatory Attorney Mitchell E. Parrish, JD, CIP
Presentation Topics
Webinar Overview Electronic Consent Electronic Technologies Electronic Data Storage Electronic Data Monitoring
Webinar Overview
Electronic Technologies in Research
Electronic technologies are being viewed as an increasingly popular and effective tool in all aspects of human subject research
The FDA and OHRP have not produced much guidance on the use of electronic technologies
Why do we need to discuss electronic technologies in research?
Electronic Technologies in Research
Even if the FDA or OHRP produces
guidance or regulations applicable to
electronic technologies, innovation ensures
that such technologies will constantly
evolve forever leaving questions
unanswered and scenarios unaddressed
Using Electronic Technologies in Research
Sponsors, CROs, Institutions, and Researchers need to understand the applicable FDA and DHHS regulations to ensure compliance when using electronic technologies
All parties working with and submitting to the IRB can benefit from knowing how an IRB applies the regulations and responds to the use of electronic technologies in research
Electronic Consent Regulatory & IRB Considerations
Examples
When is electronic consent appropriate? Online Survey Studies
• Patients are asked their activity and pain level 3 months after receiving composite femoral components for hip arthroplasty
Screening • Potential subjects are asked a series of questions
about their health history to determine eligibility in a study testing a novel drug for Rheumatoid Arthritis
Examples
Submitting Biological Specimens via Mail/Fed Ex etc. • A company conducting genetics research is collecting buccal
samples for analysis
Previously collected tissue research • Cosmetic surgery patients are contacted for their consent to
use their discarded tissue to test a new topical drug for hair growth
In-person paperless survey research • Patients with pancreatic cancer at an outpatient oncology
infusion site are provided an iPad in which to answer questions about experienced side effects
Benefits of Electronic Consent
For Participants Convenience – Where unnecessary, participants do not
have to commute to the research site
Less pressure – Participants can review the consent form on their own and with family without feeling pressure to sign right away
More Informed – Subjects can take their time reading through the form thereby making a more informed decision
There are potentially multiple and varied benefits to electronic consent:
Benefits of Electronic Consent
For Researchers Higher Enrollment? – No commute, less pressure, and
completing research on their own time may increase enrollment
Convenience – No in-person appointment scheduling
No travel reimbursement – No commuting or parking costs
There are potentially multiple and varied benefits to electronic consent:
Benefits of Electronic Consent
For Researchers (cont.) Paperless – Ability to manage documents electronically
Increased capability – Can conduct studies with a larger participant base and more varied types of research
Challenges of Electronic Consent
For Participants Consent discussion – More difficult or limited consent
discussion with research staff
Confidentiality – Who has access to and can view consent documentation or answers to screening questions
There are some potential concerns with electronic consent:
Challenges of Electronic Consent
For Researchers Expensive – High initial expense for infrastructure and
technology to manage online documents and establish systems to validate electronic consent
Verification – Is the electronic consent legitimate and actually from the participant
Compliance – Is the electronic consent acceptable to auditors and in compliance, where applicable, with 21 CFR Part 11
There are some potential concerns with electronic consent:
Using Electronic Consent
When the type of research warrants electronic consent and the benefits outweigh the challenges, then consider using electronic consent
Types of Electronic Consent
Two types
1) Full “signature” (or mark) – A computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature 21 CFR 11.3(b)(7)
• Electronic or digital signature treated as though signature were handwritten on paper
• Example: signature on the credit card scanner when you buy groceries
• A full signature is currently usually not an option unless conducting in-person research using an onsite computer, electronic tablet, or device with an attached magnetic pen
Full Signature
However, such signature must be legally valid within the jurisdiction where the research is conducted
• What if research is conducted online?
• For more information, see OHRP Informed Consent – FAQs
OHRP states that it does allow electronic signatures
Full Signature OHRP permits IRBs to accept electronic
signatures if the IRB has considered the following:
• How the electronic signature is being created,
• If the signature can be shown to be legitimate, and
• If the consent document can be produced in hard copy for review by the potential participant
Example: Software that utilizes encryption technology and public key infrastructure (such software is available from RSA, Entrust, Verisign, GeoTrust and ActivCard)
Types of Electronic Consent
Two types
2) Indication of consent other than a full signature
• Example: Click on the box to consent
• Example: By submitting this survey you are consenting to participate in the research
Indication of Consent
45 CFR 46.109(c) and 21 CFR 56.109(c) both say . .
• “An IRB shall require documentation of informed consent . .”
• However, both regulations do permit an IRB to waive documentation of informed consent
Therefore, a valid full signature is required unless the IRB waives documentation of informed consent
DHHS and FDA regulations state that an IRB must require documentation of informed consent:
Indication of Consent
There are two sets of criteria in which a study may qualify for a waiver of documentation of consent under the DHHS regulations • 45 CFR 46.117(c)(1) – 1) the only record linking the subject
and the research is the consent document and 2) the principal risk of the research is the potential harm from a breach of confidentiality
• 45 CFR 46.117(c)(2) – 1) the research presents no more than minimal risk of harm to subjects and 2) involves no procedures for which written consent is normally required outside of the research context
Waiver of Documentation of Consent:
Indication of Consent
There is one set of criteria in which a study may qualify for a waiver of documentation of consent under the FDA regulations • 21 CFR 56.109(c)(1) – 1) the research presents no more
than minimal risk of harm to subjects and 2) involves no procedures for which written consent is normally required outside the research context
Waiver of Documentation of Consent:
Indication of Consent
Waiver of Documentation of Consent:
Where a waiver of documentation of consent is granted, documentation that subjects will receive appropriate information and will consent is still required
Therefore, the IRB must still review and approve the “consent form” or “information sheet” that participants will read in electronic format
Indication of Consent
Information Sheet:
All elements of consent required by 45 CFR 46.116 and 21 CFR 50.25 must be present
However, keep document brief • Consider what elements are not required
• Consider whether HIPAA Authorization language is necessary. If not, do not include. Otherwise, consider a stand alone HIPAA Authorization
Electronic Consent
Key Take Away Electronic consent is only appropriate for some
types of research
When appropriate, consider the benefits and challenges of implementing electronic consent
Ensure compliance with the regulations based on the electronic consent obtained
Electronic Technologies To
Facilitate Consent
Regulatory and IRB Considerations
Examples
Podcasts • A Principal Investigator records herself explaining the
study on a digital player for playback to potential participants
Embedded comments in consent forms • Various sections of an online consent form have a link
to a voice recording adding explanatory information
Electronic Technologies to help facilitate consent:
Examples
Electronic Technologies to help facilitate consent: Videos
• In addition to a written form, there is a video explaining the study that includes diagrams, charts, and demonstrates various procedures
Interactive website • Potential participants are provided access to a website
containing multi-media that they can navigate to help further explain information about the study
Benefits of Electronic Technologies
For Participants True informed consent – Not every person learns the same
(Auditory, Visual, Tactile). Supplementing consent forms and consent discussions may help participants better understand the research
Less anxiety – A participant who better understands the research may have less anxiety over their participation
More engaged – A participant engaged in the consent process is more likely an engaged participant in the research
There are potentially multiple and varied benefits to electronic technologies:
Benefits of Electronic Technologies
For Researchers True informed consent – Not every person learns the same
(Auditory, Visual, Tactile). More compliant, more ethical
More engaged – A participant engaged in the consent process is more likely a compliant participant
Higher enrollment? – Informed and engaged potential participants are more likely to enroll
Industry leader – Paving the way to obtaining true informed consent improves the clinical research industry
There are potentially multiple and varied benefits to electronic technologies:
Challenges of Electronic Technologies
For Participants Ineffective – Various electronic technologies are not going
to improve the consent process for some participants and may simply result in a participant’s unnecessarily expended time
There are not many potential concerns with electronic technologies:
Challenges of Electronic Technologies
For Researchers Expensive – Extra money and time to develop
technologies to facilitate consent and the creation of more material for the IRB to review
Ineffective – After investing money in developing technologies, will the technologies serve their purpose
There are some potential concerns with electronic technologies:
Using Electronic Technologies
When the type of research and consent process warrants using electronic technologies to facilitate consent and the benefits outweigh the challenges, then consider implementing such technologies
IRB Review of Electronic Technologies
FDA and DHHS regulations require the IRB to review all research activities including those relating to informed consent 21 CFR 56.109 & 45 CFR 46.109
“Informed consent is more than just a signature on a form, it is a process of information exchange that may include, in addition to reading and signing the informed consent document, subject recruitment materials, verbal instructions, question/answer sessions and measures of subject understanding. Institutional Review Boards (IRBs), clinical investigators, and research sponsors all share responsibility for ensuring that the informed consent process is adequate. Thus, rather than an endpoint, the consent document should be the basis for a meaningful exchange between the investigator and the subject.” (FDA Information Sheet – A Guide to Informed Consent)
IRB Review of Electronic Technologies
What actually requires IRB review?
• Most technologies will require IRB review, which may be reviewed with the study, the consent form, or as individual materials
• Work with your IRB to determine what requires review and how best to submit the technologies for review Example: The script of a video or podcast can be
reviewed by the IRB prior to filming or recording to reduce the chance that costly revisions are not required once the video or podcast is finalized
Any technologies, known or novel, can be used to facilitate the consent process
IRB Review of Electronic Technologies
Case Study An outpatient oncology clinical trial site has a consent form approved for a phase II trial testing the safety and efficacy of a drug to treat pancreatic cancer. Along with the consent form, the site also received IRB approval for its interactive website to facilitate consent. The website contains, as an example, graphs; charts; videos of how to complete subject diaries; and recordings of research coordinators explaining precautions for participants while suffering from a weakened immune system
IRB Review of Electronic Technologies
Questions
1) If the site updates its website to include photo images of the approved consent form, does the addition of the images require IRB review?
2) If the site updates its website to include language taken directly from the approved consent form, does the addition of this language require IRB review?
3) If the site updates its website to include language taken directly from the approved consent form, but modified to have the benefits section highlighted and underlined, does the addition of this language require IRB review?
Electronic Technologies
Key Take Away Electronic technologies for facilitating consent are
only appropriate for some types of research and consent processes
When appropriate, consider the benefits and challenges of implementing electronic technologies
Obtain IRB approval after working with your IRB to determine how best to submit your electronic technologies
Electronic Data Storage
Regulatory & IRB Considerations
Examples
Studies conducted entirely with electronic data storage • Online Survey Studies conducted throughout the United
States
Studies conducted partially with electronic data storage • Phase IV registry studies where charts are retrospectively
reviewed and data is uploaded into an electronic database
Studies conducted with paper and electronic data storage • Phase III clinical trials at sites where the site uploads all trial
data recorded on paper into an electronic database
Benefits of Electronic Data Storage
Paperless – Less storage space required; environmentally friendly; convenient access for staff
Remote Monitoring – Sponsors and CROs do not have to be onsite to examine charts/data etc.; Investigators can review data/charts from multiple sites
Efficiency – Eliminates steps in processing and handling documents
Challenges of Electronic Data Storage
Expensive – High initial expense for infrastructure and technology to manage online documents and controlled/secure access to data
Confidentiality – Potential for breach of online system or system errors
Compliance – Requires compliance with 21 CFR 11
• Validation to ensure accuracy, reliability, consistency
• Accurate generation of records for agency inspection
• Protection of records to always allow retrieval
• Controls to limit access to authorized individuals
Challenges of Electronic Data Storage
Computer generated audit trails
Operational system checks to enforce sequencing of events
Checks to ensure only authorized users can/access use the system or modify records
Checks to ensure validity of the source of data input or operational instruction
Process to ensure those who develop, maintain, or use the electronic data system have the appropriate education, training, and experience
Written policies holding individuals accountable for inappropriate use of the system
Change control process
Implementing Electronic Data Storage
Determining whether to implement electronic data storage is a business decision, so where does IRB review come into play?
IRB Review of Electronic Data Storage
FDA and DHHS regulations require the IRB to ensure “there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data” 21 CFR 56.111(a)(7) & 45 CFR 46.111(a)(7)
Sponsors, CROs, Institutions, and investigators all need to continue providing enough information, so the IRB can ensure there are adequate provisions to protect the confidentiality of electronically stored data
However, please note that IRB is not the expert in electronic systems and is unable to advise on the implementation of such systems
IRB Review of Electronic Data Storage
New Common Rule In the July 25, 2011 Federal Register, DHHS issued
an Advance Notice of Proposed Rulemaking communicating proposed changes to the Common Rule (http://www.gpo.gov/fdsys/pkg/FR-2011-07-26/html/2011-18792.htm)
DHHS re-affirms that there are no specific data security protections for IRB reviewed research beyond the requirement that “there are adequate provisions to protect the privacy of subjects and confidentiality of data”
IRB Review of Electronic Data Storage
New Common Rule DHHS proposes standards in data security for all
human subject research to follow, calibrated to the level of identifiability of information being collected
Rational – IRBs were not designed to evaluate risks to data privacy and confidentiality
Rational – Uniform specific standards will help assure risks to privacy and confidentiality are addressed without requiring IRBs to conduct a review of such risks
Electronic Data Storage
Key Take Away Whether to implement electronic data storage is a
business decision based on the benefits and challenges
Provide the IRB with sufficient information explaining and assuring that the confidentiality of electronically stored data is protected
Be aware of possible future changes and standards for electronic data storage put forth in the new Common Rule
Electronic Data Monitoring
Regulatory & IRB Considerations
Examples Minimal risk online survey research
• The type of research being conducted will determine the appropriateness of electronic data monitoring
Phase I drug trial
• Most research can utilize electronic data monitoring for at least part of a study. Some research may almost entirely utilize electronic data monitoring
Examples What can you monitor electronically (“remotely,” or
“centrally”)? • Data results obtained or entered electronically (e.g.,
Laboratory results) • Subject visit schedule • Reported protocol violations (e.g., missed visit,
missed lab) • Recorded adverse events • Query issue & query resolution • Site training records • Communications between site & monitor
Benefits of Electronic Data Monitoring
Investigative site support – Consistent, centralized, real time support for site
• Examples: Sites can review data with monitor if there are questions; monitor can notify the site if it appears a subject is close to being out of window on a follow-up visit
Timely – Real time review, clarification, and correction of recorded data
Efficiency – Allows an on-site monitor to focus on critical safety and efficacy data (electronic monitor can handle the more repetitive tasks, like data queries)
Expense reduction – Less frequent on-site monitoring required
Challenges of Electronic Data Monitoring
On-site effect – Likely that only an on-site visit can . . .
• Identify source data errors and missing data • Assess the familiarity of the site’s study staff with the
protocol and investigational product • Assess compliance with the protocol and investigational
product accountability • Provide a sense of the site’s overall quality in conducting the
trial
Duplicate Monitoring – If an on-site visit is required, the monitoring on-site visit may duplicate work already completed
Compliance – Requires compliance with 21 CFR 11 and appropriate systems to ensure confidentiality of data shared online
Using Electronic Data Monitoring
With definite benefits and challenges to using electronic data monitoring, how do you know when to use such monitoring?
Using Electronic Data Monitoring
FDA Guidance for Industry: Guideline for the Monitoring of Clinical Investigations, January 1988 – recently withdrawn
• This guidance summarized that “the most effective way” to monitor an investigative site was to maintain personal contact between the monitor and the investigator throughout the clinical investigation
• Note that this was issued prior to mainstream use of email, internet, internet meetings, etc. Withdrawing this guidance provides significant support for electronic monitoring
Using Electronic Data Monitoring
FDA drug regulations require a sponsor to ensure “proper monitoring of the investigation(s)” and “that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND” 21 CFR § 312.50 • Applies to in-person or electronic monitoring
FDA device regulations states that sponsors are responsible for “ensuring proper monitoring of the investigation,…” 21 CFR § 812.40 • Applies to in-person or electronic monitoring
Using Electronic Data Monitoring
ICH E6(R1) – this GCP guideline includes a specific section on Monitoring, emphasizing that “the sponsor should ensure that the trials are adequately monitored” and that “the sponsor should determine the appropriate extent and nature of monitoring.” This determination may be based on considerations such as “objective, purpose, design, complexity, blinding, size, and endpoints of the trial”
Using Electronic Data Monitoring “We had been issuing some warning letters to sponsors citing inadequate monitoring, and one of the things that we had heard as members of the Clinical Trials Transformation Initiative (CTTI) committee was that this was leading some sponsors to take a 100% source data verification… Companies were saying, ‘well, FDA is sending out warning letters saying that we have inadequate monitoring, so we’re just going to throw more monitors out there.’ I don’t think that really was the message we were trying to get across with our warning letters. What we wanted to try to incorporate is an idea that there should be a risk assessment and that monitoring should be geared toward the risk”
Leslie Ball, M.D., Director of CDER Division of Scientific Investigations, 2010
Using Electronic Data Monitoring
Draft FDA Guidance for Industry: Oversight of Clinical Investigations: A risk-Based Approach to Monitoring, August 2011
• FDA recommends monitoring plans tailored to the specific human subject protection and data integrity risks of the trial
• The monitoring plan should identify the various methods intended to be used and the rationale for their use
The new approach proposed in the Draft Guidance is risk-based: it focuses on the most critical data elements (i.e. the quality and integrity of the clinical trial data), arguing that this approach is more likely to ensure subject protection and overall study quality, rather than routine visits to all clinical sites and 100% data verification
Using Electronic Data Monitoring
When considering electronic monitoring, you should perform a risk assessment that generally considers: • the types of data to be collected in a clinical trial, • the specific activities required to collect these data, and • The range of inherent potential safety and other human
subject protection concerns Example: On-site visits are critical early in a study,
especially if the protocol is complex or includes novel procedures with which site staff or investigators are unfamiliar
Example: On-site visits are not necessarily critical for follow-up visits a year after dosing concludes
Provide support for your monitoring plan to the IRB
Electronic Data Monitoring
Key Take Away Although the FDA guidance is draft, the withdrawal of the
previous guidance and the flexibility of ICH E6(R1) indicates that the industry is moving towards more electronic monitoring
Move away from applying the same monitoring plan to studies with widely differing designs, risk levels, and data sets with varying sophistication levels
With electronic monitoring evaluate, plan, and perform a risk assessment of the potential monitoring activities to determine appropriateness
Webinar Summary
Overarching Example “Mytrus 16-wk Paid Overactive Bladder Clinical
Trial for Women”
http://www.youtube.com/watch?v=0fEx5V45zp4
Webinar Summary
Know the benefits and challenges of each electronic technology you are considering implementing
Understand the most applicable regulations and also what the IRB expects to see when reviewing the research
If there are questions, contact the IRB for assistance
Questions & Answers
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