OHRP/FDA offer final guidance on electronic informed consent
Saturday, April 1, 2017
On December 15, 2016, the Office for Human Research Protections (OHRP) of the U.S. Department of Health and Human Services (HHS) and the FDA published final guidance aimed at providing answers to commonly asked questions about using electronic informed consent (eConsent)in clinical investigations. The guidance applies to “electronic systems and processes that may employ multiple electronic media to obtain informed consent for both HHS-regulated human subject research and FDA-regulated clinical investigations of medical products, including human drug and biological products, medical devices, and combinations thereof.”1 This guidance finalizes the draft guidance Use of Electronic Informed Consent in Clinical Investigations – Questions and Answers that was issued in March 2015. The final guidance was developed in collaboration with FDA and OHRP and is issued as a joint final guidance.
If the study is conducted or supported by HHS and involves an FDA-regulated product, both sets of regulations must be followed. Where the regulations differ, the regulations that offer the greater protection to human subjects should be followed. The guidance describes the current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.
According to the guidance, investigators may use eConsent to help: 1) ensure protection of the rights, safety, and welfare of human subjects; 2) facilitate the subject’s comprehension of the information presented during the eConsent process; 3) ensure that appropriate documentation of consent is obtained when electronic systems and processes that may employ multiple electronic media are used to obtain informed consent; and 4) ensure the quality and integrity of eConsent data included in FDA applications and made available to FDA during inspections. For the purposes of this guidance, electronic informed consent refers to the use of electronic systems and processes that may employ multiple electronic media, including text, graphics, audio, video, podcasts, passive and interactive web sites, biological recognition devices, and card readers, to convey information related to the study and to obtain and document informed consent.
The final guidance clarifies the following: 1) how to present information in the eConsent to the subject; 2) how and where to conduct the eConsent process; 3) how and when questions from subjects should be answered; 4) steps that may be taken to facilitate the subject’s understanding; 5) how to convey additional information to the subject during the course of the research; 6) how to use electronic signatures to document eConsent; 7) how to verify the identity of the subjects who will be electronically signing the informed consent; 8) how to use electronic informed consent for pediatric studies; 9) how to provide copies of the eConsent to the subject; 10) steps that may be taken to ensure privacy, security, and confidentiality of the eConsent information; 11) how to obtain Health Insurance Portability and Accountability Act (HIPAA) authorizations for research electronically; 12) what eConsent materials the investigator should submit to the institutional review board (IRB); 13) the IRB’s responsibilities in the eConsent process; 14) the eConsent documentation required for FDA submission with applications; 15) steps to ensure that eConsent materials are archived appropriately for FDA-regulated clinical investigations; and 16) what eConsent materials or documents FDA will require during an inspection.
Changes and key points in the guidance
Below are key points to consider in the guidance, according to clinical research professionals who have evaluated it:
- The eConsent must contain all elements of informed consent required by HHS and/or FDA regulations. It also may be used to either supplement or replace paper-based informed consent processes to best address the subject’s needs throughout the course of the study. “For example, some subjects may prefer one method over another. Other subjects may have difficulty navigating or using electronic systems because of, for example, a lack of familiarity with electronic systems, poor eyesight, or impaired motor skills. In such cases, the eConsent process may not be appropriate for these subjects.”1 Therefore, subjects should have the option to use paper-based or electronic informed consent methods completely or partially throughout the informed consent process. “Moreover, in some circumstances, it may be appropriate for investigators or study personnel to assist subjects in using the eConsent technology. For example, study personnel may help the subject navigate the consent by clicking on links for the subject.”
- The investigator is responsible for ensuring that legally effective informed consent is obtained before that subject takes part in the study. If the investigator delegates this responsibility, the responsibility should be delegated to an individual qualified by education, training, and experience to perform this activity. The investigator cannot delegate authority to obtain informed consent to the electronic system.
- If any or all of the consent process takes place remotely and is not personally witnessed by study personnel, the electronic system must include a method to ensure that the person electronically signing the informed consent is the subject who will be participating in the research study or is the subject’s legally authorized representative (LAR). Examples of various methods that could be used include verification of a state-issued identification or other identifying documents or use of personal questions, biometric methods, or visual methods.
- EConsent software tools in FDA-regulated research must meet the requirements of 21 CFR 11. “FDA regulations found at 21 CFR part 11 set forth the criteria under which FDA considers electronic records, electronic signatures, and handwritten signatures executed to electronic records to be trustworthy, reliable, and generally equivalent to a handwritten signature executed on paper,” the guidance says. “In order to be considered equivalent to full handwritten signatures, electronic signatures must comply with all applicable requirements under 21 CFR part 11. The electronic system must also capture and record the date that the subject or subject’s LAR provides consent.”
- HHS and FDA regulations require that the person signing the informed consent (i.e., the subject or the subject’s LAR or the parents or guardians of subjects who are children) be given a copy of the written informed consent form. “The copy provided to the subject can be paper or electronic and may be provided on an electronic storage device or via email,” the guidance says. “If the copy provided includes one or more hyperlinks to information on the Internet, the hyperlinks should be maintained and information should be accessible until study completion.”
- HIPAA authorizations may be obtained electronically, provided that the signature of the subject (or the subject’s personal representative) is a valid electronic signature under applicable laws and regulations.
- The IRB must review and approve the eConsent and any amendments to the eConsent that the subject will receive and view. The IRB must maintain and retain copies of materials that have been reviewed in accordance with 45 CFR 46.115 and 21 CFR 56.115. The IRBs should also review any optional questions or methods used to gauge subject comprehension of key study elements. In addition, the IRB should review the usability of the eConsent materials to ensure that they are easy to navigate. If the program uses hyperlinks to convey study-related information, the IRB should review the contents to which subjects are referred in order to determine if the study-related information that has been supplied is accurate and appropriate. Because websites are often modified over time, IRBs must maintain the version of the website information that contains the study-related information that the IRB reviews and approves, either electronically or as a hard copy.
- The eConsent process should incorporate procedures to ensure that electronic documents can be archived appropriately and that all versions of the IRB-approved eConsent can be retrieved easily. All procedures must be in compliance with applicable FDA regulations for electronic records.
Quorum Review IRB in Seattle gave a few tips for researchers trying to decide on eConsent products in light of the final guidance.
- Look to the most rigorous system requirements that may apply to a situation. “For us, this typically means expecting a product to comply with Part 11, HIPAA, and The Health Information Technology for Economic and Clinical Health Act.”
- For IRBs, establish clear review guidelines for eConsent and, if feasible, recruit an IRB member or consultant with relevant IT expertise.
- Require that a prospective eConsent vendor verifies in writing that its product meets all necessary requirements; ideally, the verification would come from a reliable third party rather than self-reporting.
“The often-expressed concerns about security, privacy, and systems compliance in an [eConsent] system are understandable,” writes Jim Gearhart for Quorum. “This latest joint guidance from OHRP and the FDA shows routes to alleviating them.”2
eConsent in practice
Electronic consent came to the forefront in June 2011 when Pfizer announced that it was conducting the first-ever randomized clinical trial under an investigational new drug (IND) application that “manages study participation entirely using electronic tools and allows patients to participate in the clinical trial regardless of their proximity to clinical sites.”3 The pilot project, Research on Electronic Monitoring of Overactive-bladder Treatment Experience (REMOTE), was developed in collaboration with and approved by FDA. The trial evaluated tolterodine tartrate (Detrol LA) for overactive bladder. Pfizer and its research partners hoped to replicate the results of a previously completed Phase IV Detrol LA trial, and in this way “begin to validate virtual, patient-centered approaches to clinical research.”
“With the REMOTE virtual trial pilot, for the first time we can make it possible for patients to participate in clinical trials without having to visit physical sites,” announced Pfizer executive vice president and chief medical officer Freda Lewis-Hall at that time. “Studies like REMOTE could make biomedical science much more accessible to people who have long been excluded from or under-represented in clinical trials. Putting research within reach of more diverse populations has the potential to advance medical progress and lead to better outcomes for more patients.”
The REMOTE trial was the first-ever randomized “virtual” clinical trial under an IND application to secure patient consent online using video/multimedia and online testing. Study investigators planned to ship all blinded study medication to patients at home rather than dispensing it at a clinic visit. Researchers would manage study conduct remotely, and share clinical trial data and results with patients. Investigators in the REMOTE trial had the goal of enrolling 600 patients from about 10 states across the United States. Mytrus, a Davis, California, clinical technology and services company, added support to the trial with its electronic informed consent and data collection tools.
By May 2012, however, the study had been terminated, having enrolled only 18 patients. In an article published in Contemporary Clinical Trials in July 2014, REMOTE investigators explained what went wrong — and what went well.4 Information used to validate the identity of potential subjects were not always publicly available. The date entry/interface needed improvement, and confirmation emails from Pfizer would sometimes go to subjects’ SPAM folders. One of the investigators said that parts of the process were found to be “quite complicated and tedious,” and that patients were unsure of putting their health insurance information online.5 Pfizer, however, reported being pleased with the online video-based informed consent and the electronic data capture tools used in the trial. The consent was standardized across sites, and study subjects had their comprehension tested with a quiz.6
Anthony Costello, CEO of Mytrus, responded during that period to a now-deleted blog post that wondered about how virtual trials can compare to on-site studies, where site staff can offer support, build trust, or contribute to recruitment and retention. “The writer is correct that there is an obvious value sites can bring to trials by serving as the trusted ‘human’ component of the research. Unfortunately, the notion that all patients are always carefully handled through some sort of nurturing experience with their medical providers is not really supported with real evidence. Moreover, it’s wishful thinking that sites do a uniformly good job of enrolling trials, following patients, focusing on retention, entering timely data, and any number of other critical study functions, to say nothing of the fact that most studies are simply not available to most patients because they don’t live close enough to a site. For all of these reasons, direct-to-patient studies make a lot of sense — especially for a patient who is not choosing between a local site and a remote site — they’re choosing between interacting with a remote site or not participating at all.”7
REMOTE investigator Craig Lipset, head of clinical innovation within global product development at Pfizer, said the company was “already using the output from the modules within REMOTE that were successful, incorporating tools such as remote monitoring, eConsent, and other components in our studies wherever they can add value by improving patient engagement, participation, and trial efficiency.” Although being transparent about the problems with the trial has opened investigators to criticism, it has also sparked other companies to conduct their own experiments and investments improving study conduct and patient participation, he says. “The REMOTE study only carried the ball so far down the field, and we hope others can pick up and continue to move us all farther downfield toward our desired goal.”4
In August 2015, Mytrus announced that its software platform for eConsent had received approval by Health Research Authority, a division of Britain’s National Health Service, to be used in a trial in England in which eConsent technology is being used for the first time. The trial, said to be studying an autoimmune disease drug candidate, is reported to have begun in July and is using Mytrus’ eConsent technology alongside traditional paper forms. “By running both systems in parallel, the organizers of the study hope to gather data showing how the new technology compares with paper,” FierceBiotech reports.8
On March 7, 2016, Mytrus announced that its eConsent technology also would be used to support the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness) trial. The coordinating center for ADAPTABLE is the Duke Clinical Research Institute (DCRI) in Durham, North Carolina. ADAPTABLE will enroll 20,000 patients and is designed to compare the effects of two different daily doses of aspirin for patients diagnosed with established atherosclerotic cardiovascular disease. Mytrus’ virtual trial platform also will be used to randomize patients through an interactive web portal, follow them throughout the 30-month study, and provide a platform for investigators and clinical staff to interact with patients and collect patient-reported outcomes using web-based technologies. Matthew Roe, of DCRI and a co-principal investigator for the trial, says, “ADAPTABLE has the potential to transform how we leverage electronic health records to identify potentially eligible patients for a clinical trial, use web-based technologies to facilitate patient enrollment and randomization, and engage patients from protocol design through analysis in a clinical trial.”
Hospitals and clinics that are part of large, integrated research networks participating in the initiative are inviting potential patients to participate in the ADAPTABLE trial. Potential subjects will be directed to a web portal accessible through a standard web browser on a computer, tablet, or smart phone. Patients will be introduced to the study through multimedia tools that offer explanations in English or Spanish. During the term of the study, participants will receive text messages and email reminders on a scheduled basis to log in and enter specific health information and patient-reported outcomes. “This trial is ideal for a virtual model because the trial design is pragmatic, and the product being tested (aspirin) is a widely available over-the-counter therapy,” says Mytrus’ Costello.
“Many studies conducted in the healthcare and clinical trial setting have shown that we currently are falling short when it comes to providing our patients with the information they need to truly give informed consent,” says Jeffrey Litwin, cofounder of Patient Genesis in Fairfield, NJ, in an article for Applied Clinical Trials website. “Providing patients with video educational tools and retention aids that explain information in layman’s terms and in their native language improves both patient recall and comprehension.” EConsent has been used worldwide and is accepted by IRBs; however, the overall adoption rate has been slow, he says. “The regulatory safeguards for documentation and reConsenting, the ease of use for ICF (informed consent form) approval on a local level, and the benefits to the patient will hopefully move the ICF from being one of the last remaining bastions of the paper process into the modern digital era.”9
- Use of electronic informed consent in clinical investigations – questions and answers; Guidance for institutional review boards, investigators, and sponsors. Office for Human Research Protections December 2016 Available at https://www.hhs.gov/ohrp/regulations-and-policy/guidance/use-electronic-informed-consent-questions-and-answers/index.html#. Accessed March 5, 2017.
- Gearhart J. For electronic informed consent, “just following the rules” may not be straightforward. Quorum January 31, 2017. Available at http://www.quorumreview.com/fda-eic-guidance-to-follow-existing-rules-may-not-be-as-straightforward-as-it-sounds/. Accessed March 5, 2017.
- Pfizer conducts first “virtual” clinical trial allowing patients to participate regardless of geography. Pfizer Inc. June 7, 2011 Available at http://www.pfizer.com/news/press-release/press-release-detail/pfizer_conducts_first_virtual_clinical_trial_allowing_patients_to_participate_regardless_of_geography. Accessed March 5, 2017.
- Orri M, Lipset CH, Jacobs BP, et al. Web-based trial to evaluate the efficacy and safety of tolteodine ER 4 mg in participants with overactive bladder: REMOTE trial. Contemp Clin Trials 2014;38:190-97.
- Taylor N. Pfizer director defends virtual trial after recruitment struggle. Outsourcing-Pharma.com. March 6, 2012. Available at http://www.outsourcing-pharma.com/Clinical-Development/Pfizer-director-defends-virtual-trial-after-recruitment-struggle/?c=qendTuKNp6E6rdcFL8JoRQ%3D%3D&utm_source=newsletter_daily&utm_medium=email&utm_campaign=Newsletter%2Bdaily. Accessed March 5, 2017.
- Meehan L. Results of first ever REMOTE clinical trial. June 11, 2014. Polaris Compliance Consultants Inc. Available at http://polarisconsultants.blogspot.com/2014/06/results-of-first-ever-remote-clinical.html. Accessed March 5, 2017.
- Henderson L. REMOTE trial not a remote idea. Appl Clin Trials Available at http://www.appliedclinicaltrialsonline.com/remote-trial-not-remote-idea. Accessed March 5, 2017.
- Taylor NP. Mytrus makes electronic informed consent breakthrough in UK. August 31, 2015 Available at http://www.fiercebiotech.com/r-d/mytrus-makes-electronic-informed-consent-breakthrough-u-k. Accessed March 5, 2017.
- Litwin J, Engagement Shift: Informed consent in the digital era. Appl Clin Trials Available at http://www.appliedclinicaltrialsonline.com/engagement-shift-informed-consent-digital-era-0?pageID=1. Accessed March 5, 2017.
By Sue Coons, MA
This article was reprinted from Research Practitioner, Volume 18, Number 2, March-April 2017.