Common Problems in Informed Consent Jeri R. Barney, JD, MS Michele Antisdel, MBA/CCRP HRPP Compliance Manager IRB Regulatory Analyst Human Research Protection Program (HRPP) May 16, 2013

Discussion Consent Process Consent Requirements Common Problems in Informed Consent Suggestions for Improvement

Consent Process

What is Informed Consent? Information Technology Services 4/5/2017 What is Informed Consent? Example of Ethical Principle of Respect for Persons Not a document, but a process Starts at initial contact (e.g., recruitment) Respect for persons- Autonomy—letting people choose by giving them the info to weigh benefit v risk for THEM Process is meant to educate the subject about the study and allow them to make the decision regarding whether or not to participate. The consent process takes place throughout the duration of the subjects involvement in the study. Always invite them to ask questions at each visit, make sure they still have an understanding what is being done and what they are required to do Initial contact- Screening scripts or tools should have a description of the study for participants Subjects will remember what is said at screening (sometimes will mis-remember too!!) So let’s say you hang a flyer for ‘people who can’t hop on one foot’-the subject calls and the screener could say “this is a study for people who can’t hop on one foot. If you are eligible for the study , you would come to our clinic located at 300 Cedar St where we will teach you how to hop on one foot using one of two methods. It involves 5 visits and will take about 8 weeks to complete. T here are no medications involved. If you are interested, I would like to ask you some questions to see if you might be eligible to participate, is that ok?’ (C) Copyright, 2000 Yale University. All rights reserved.

Informed Consent Process Information Technology Services 4/5/2017 Informed Consent Process Continues through study participation an informed participant is better able to adhere to the protocol and therefore provide evaluable data research staff members are obligated to share any new information related to subject’s participation (e.g., newly identified side effects, etc) If subjects aren’t educated about the study, it is hard for them to follow the protocol, may say “I didn’t know there were no medications involved” and they may be more likely to drop out and no one wants that New info -may require consent addendum—more on that a little later (C) Copyright, 2000 Yale University. All rights reserved.

Informed Consent Process Information Technology Services 4/5/2017 Informed Consent Process Handing a participant the consent document and asking them to read and ask questions is NOT Informed Consent Bullet 1 Informed consent does not mean you have to read the entire document to them word for word, especially when some consent forms can be up to 20 pages! Informed consent is a dialog between you and your subject with a give and take. One tip is to read the consent to yourself and highlight important points to develop a “script” –rehearse this with someone else involved in the study (if possible) to make sure that you have provided enough information—then, practice on someone NOT involved in the study But even when you develop a script highlighting the important points, still always keep the document in front of you for reference And remember, the subjects will still be given a copy of the consent document to read with all the finer details in it. And you will give them time to read the document and consider whether they want to take part. (C) Copyright, 2000 Yale University. All rights reserved.

Consent Requirements

8 Basic Elements in an ICF The following eight basic elements of informed consent are required to be provided in the course of the consent process. The investigator must ensure that these elements and any others required by the IRB are presented in such a manner as to facilitate the prospective participant’s ability to understand involvement in the research study. 1. Invitation to Participate 2. Risks 3. Benefits 4. Alternatives to Participation 5. Confidentiality Statement 6. Compensation for Medical Treatment 7. Who to contact (and when) with problems/how to withdraw 8. Voluntary Participation 1. A statement that the study involves research, an explanation of the purpose of the research, the expected duration of participation, a description of the procedures, and identification of the experimental procedures. 2. A description of any reasonably foreseeable risks or discomforts. 3. A description of any benefits to the subject or to others that might be reasonably expected from the research. 4. Disclosure of appropriate alternative procedures or courses of treatment, if any, that may be advantageous to the subject. 5. A statement describing the extent, if any, to which confidentiality of records identifying the participant will be maintained including as appropriate: (a) what records may be examined by the sponsor, the IRB, other University personnel, the Food and Drug Administration (FDA), or other regulatory agencies, (b) whether or not the data collected will be retained, and, if so, for what purpose and for what period of time, or when the data will be de-identified and/or destroyed, (c) what procedures will be put in place to ensure that unauthorized individuals will not have access to this information, and (d) the limitations (if any) to these confidentiality procedures such as legal reporting requirements for specific diseases and in the case of suspected child or elder abuse. 6. For research involving more than minimal risk, an explanation as to whether or not any compensation and medical treatment are available if injury occurs to the participant and if so, what they consist of or where further information may be obtained. 7. Identification of whom to contact for answers to questions about the research and the research participants’ rights including whom to contact when the investigator may be unavailable or to discuss any other questions, complaints or concerns and whom to contact if the participant sustains a research-related injury. 8. A statement that research participation is voluntary, that the participant may discontinue participation at any time, and that the participant’s refusal to take part or withdrawal will not involve a penalty or loss of benefits to which the participant is otherwise entitled.

Consent Requirements In addition to the 8 required elements, one or more of the following elements are to be provided to the subject when appropriate to the study: Procedures- in lay terms! Tell which are experimental Research not medical treatment & purpose of the research Possibility of unforeseeable risks The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject. A statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject. How long/duration of participation Subject responsibilities The approximate number of subjects involved in the study. For FDA regulated studies: clinicaltrials.gov In addition to the 8 required elements in the consent form, other information that should be provided to the subject so that they can make an informed decision are seen on this slide. These additional elements to be added will dependent on what is being done in the particular study. Clinicaltrials.gov: FDA regulated studies: generally interventional studies, conducted under an FDA IND or IDE, involves drug, biologic, or device manufactured in the US

Regulatory Requirements 45 CFR 46.116 (HHS) and 21 CFR 50.20 (FDA) provide the general requirements for informed consent. No investigator may involve a human being as a subject in research unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative (e.g., for a minor child this would be the parent or guardian). An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution or its agents from liability for negligence. Time to Consider: For example, avoid discussing the study then immediately asking the subject to sign consent. They should be given the opportunity to think about it, talk to family members or friends. This is especially important when the PI is also their treating physician. The subject might feel that they have to take part in the study because their treating doctor, who is also the PI, will get mad at them. Giving them the opportunity to think first, will allow them to make a solid decision, not a rushed one. Exculpatory language: For example, if an informed consent document contains language by which a subject waives his or her right to be compensated for injuries arising from participation in the research, such language would meet the definition of exculpatory language because it has the general effect of freeing or appearing to free the investigator, sponsor, and/or the research institution from malpractice, negligence, blame, fault, or guilt. An example of such language would be: I waive any possibility of compensation, including any right to sue, for injuries that I may receive as a result of participation in this research. All of our consent forms are also required to have the text “You do not give up any of your legal rights by signing this form”

Consent Requirements Continued Documentation of informed consent. Informed consent will be documented by the use of a written consent form approved by the IRB and signed by the subject or the subject's legally authorized representative. A copy is given to the person signing the form.  A consent form may be either of the following: A written consent document (consent form or compound consent and authorization form) that embodies the elements of informed. A short form written consent document stating that the elements of informed consent have been presented orally to the subject or the subject's legally authorized representative. Written Consent: This form may be read to the subject or the subject's legally authorized representative, but the investigator must give either the subject or the representative adequate opportunity to read it before it is signed Short Form: When this method is used, a witness to the oral presentation must be present. The IRB will approve a written summary of what is to be said to the subject or the representative. Only the short form itself is to be signed by the subject or the representative. However, a witness signs both the short form and a copy of the summary, and the person actually obtaining consent will sign a copy of the summary. A copy of the summary will be given to the subject or the representative, in addition to a copy of the short form. Short Form: THIS DOCUMENT MUST BE WRITTEN IN A LANGUAGE UNDERSTANDABLE TO THE SUBJECT. Short forms are often used with non-English speaking subjects in conjunction with an interpreter and tells the subject that they will be told the purpose of the study, procedures, duration of research, any procedures that are experimental, risks, discomforts, benefits, alternatives and how confidentiality will be maintained.

Consent Requirements Continued Documentation of informed consent. An IRB may waive the requirement for the investigator to obtain a signed consent form for some or all subjects if it finds either: (1) That the only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality. Each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject's wishes will govern; or (2) That the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context. If the study is FDA regulated, FDA regulations allow a waiver of informed consent only under very specific limited circumstances (21 CFR 50.23 and 21 CFR 50.24). In cases in which the documentation requirement is waived, the IRB may require the investigator to provide subjects with a written statement regarding the research. The document is called an “Information Sheet”. Information Sheets: Contain all the same elements found in the consent form, but the subject does not sign the form. An example of when this would be used is for anonymous surveys (1) or anonymous sample collections (2). Example: Anonymous blood samples for analysis. The researchers don’t care who the person is that gave the blood and don’t need any identifiable information about that person, they just want the blood. A waiver of written consent would be waived in this case. Remember, that any consent document the subject signs or is given, has to have the current IRB validation stamp on it.

Common Problems in Informed Consent

Office for Human Research Protections (HRPP) Compliance Oversight Letters OHRP reviewed 235 compliance oversight determination letters issued to 146 institutions 51% of the institutions reviewed were cited for noncompliance and deficiencies related to IRB approved informed consent documents/processes (2nd highest after deficiencies related to the initial IRB review process (56%)) 19 determinations of noncompliance for research conducted w/o legally effective informed consent

Current FDA Statistics Office of Scientific Investigations Center for Drug Evaluation & Research (CDER) (Updated: January 2013) Source http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM256376.pdf

Frequency of Clinical Investigator-Related Deficiencies Based on Post-Inspection Correspondence Issued* (CDER, FY 2012) 183 Domestic Inspections, 116 Foreign Inspections *Based on letter issue date; Inspections may have multiple deficiencies, [OSI database as of January 24, 2013] Note that this does not denote number of inspections completed in FY 2012, but rather number of inspection reports evaluated and closed in FY2012

Frequency of Clinical Investigator Related Deficiencies Based on Post-Inspectional Correspondence Issued: Official Action Indicated (OAI) Final classification* (CDER, FY 2012) 9 OAI Inspections *Based on letter issue date; Inspections may have multiple deficiencies, includes OAI untitled letters, [OSI database as of January 24, 2013] Note that this does not denote number of inspections completed in FY 2012, but rather number of inspection reports evaluated and closed in FY2012.

Examples of Common Consent Issues Failure to re-consent when new information becomes available Use of expired forms or non-validated/unapproved forms PI or consent personnel did not sign/date the form Failure to provide copies of the forms to subjects Providing all but the last page of the consent document to subjects Keeping only the last page of the consent document in study files

More Examples Failure to obtain written informed consent (neglecting to have subjects sign a consent form) Missing consent documents No documentation that consent process took place and no signed consent document on file Use of wrong form (e.g., child signing parental permission form, patient signing “healthy control” form, or subject signing the wrong version)

Even More Examples Parental permission obtained after child assent (may suggest that study interventions took place prior to securing legally effective consent) Enrolling non-English speaking subjects without using a proper interpreter (e.g., using a family member or boyfriend/girlfriend to translate) Failure to get HIPAA research (RAF) signed Changes made to the consent documents by hand AND without IRB approval (e.g., crossed out information about procedures, increased amount of payment) Explain HIPAA Reminder about reporting noncompliance

Suggestions for Improvement

Suggestions for Improvement ICF Version Control Tips Use of expired forms or unapproved forms Use of wrong form (child signing parental permission form or subject signing the wrong version) Check the Validation Box on the last page of the consent form BEFORE you consent the subject (for paper forms). For electronic forms check the header/footer for the IRB approval. In addition; check the version date to make sure you’re using the most current copy. Throw Out Expired or Outdated Versions of the consent documents IMMEDIATELY. Maintain the original in the regulatory binder for the study records but any copies of expired or outdated documents should be destroyed, and electronic copies should be moved to archive folder on computer.

Suggestions for Improvement ICF Version Control Tips Use Consent Form Log listing the different versions, version dates, expiration dates and a brief description For example: Version 1: 5/2/12 Initial approval, Healthy Control, Healthy Control with Study Drug; Version 2: 10/13/12 Amendment, Healthy Control subject payment added, Healthy Control with Study Drug subject payment added, study drug dosage reduced. Discuss New ICF Versions at regular staff meetings to inform all personnel of changes and to ensure all staff will use the correct version. If you do not have regularly scheduled meetings, be sure to inform study personnel in other ways (e.g., via email notices). Keep different versions in different folders. Color code and CLEARLY label on the folder AND in the footer of the form itself.

Suggestions for Improvement Providing Copies & Keeping Forms Failure to provide copies of the forms to subjects Providing all but the last page of the consent document to subjects Keeping only the last page of the consent document in PI files PI or consent personnel did not sign/date the form Make a checklist and an enrollment note template Immediately after signing make a copy and give the copy to subject or have subject sign duplicate copy. Create & stick to a process for where the signed ICF is kept (subject chart/folder, separate consent form binder) Educate staff so they know to provide FULL copy to subjects and keep FULL original for records Review the signed form for completeness BEFORE subject leaves and again BEFORE filing in your files DO NOT have PI pre-sign the forms

Suggestions for Improvement Amendments & Consent Addendums Changes made to the consent documents by hand AND without IRB approval (e.g., crossed out information about procedures, increased amount of payment) Failure to re-consent when new information was available Educate staff: if changes are necessary they MUST be submitted to the IRB as an amendment and approved before implementing Announce addendum in staff meeting or via email Reconsent log Check when subject’s next visit is and put a note in his/her chart and in your calendar, mark visit in red, etc. Put copy of the addendum in the subject chart or binder prior to next visit

Suggestions for Improvement Failure to Obtain Consent Failure to obtain written informed consent (forgot to have subjects sign a consent form) or failure to have HIPAA RAF signed Missing consent documents No documentation that consent process took place & no signed consent document on file • Consent should be the VERY FIRST research activity (even if subjects had a form previously mailed to them) and the VERY LAST thing you do before subject leaves • Switch to a compound form (or staple it to the consent). REMEMBER to add the RAF to reapproved consents (RAFs don’t get approved every year) • Use an enrollment note Most at risk are those researchers who see the subjects clinically as well.

Suggestions for Improvement Failure to Obtain Consent Failure to obtain written informed consent (forgot to have subjects sign a consent form) or failure to have HIPAA RAF signed Missing consent documents No documentation that consent process took place & no signed consent document on file • Double check each other; Implement a monitoring process to check for consent forms (and other issues) on a routine basis • Have process and place for signed forms to be kept • Ensure all study staff know where to find current forms • Remember what hat you’re wearing

What You Can Do Institute Processes/Form Good Habits Consent form log Always check the expiration dates on forms Double check each other Monitor your own studies on a regular basis Talk to the staff about problem trends Assign Responsibility PI is ultimately responsible One staff member responsible for consent forms Each staff member responsible for their own activities

What You Can Do Education HRPP education sessions Website policies, templates, instructions: http://www.yale.edu/hrpp/index.html Communicate with staff (meetings or emails) Communicate with IRB Regularly Ask for help If you don’t know the answer, it’s better to ask first Study start-up consultations QA/QI Reviews Call with specific questions (203) 785-4688

Call 203-785-4688 michele.antisdel@yale.edu jeri.barney@yale.edu Questions? Call 203-785-4688 michele.antisdel@yale.edu jeri.barney@yale.edu

References HRPP website: http://www.yale.edu/hrpp/ http://www.yale.edu/hrpp/policies/index.html http://www.yale.edu/hrpp/responsibility/compliance .html OHRP website: http://www.hhs.gov/ohrp/ FDA website: http//www.fda.gov/