October 13, 2015 - San Diego State University

Dear Dr. Welter:

Thank you for your October 24, 2014 report in response to our September 12, 2014 request that San Diego State University (SDSU) evaluate allegations of noncompliance with Department of Health and Human Services (HHS) regulations for the protection of human research subjects (45 CFR part 46).  Based on review of your response, we make the following determinations:

A. Determinations regarding the above-referenced research

1)  The complainant alleged that the research noted above uses an informed consent document from another study that does not adequately address the following element of informed consent required by HHS regulations for the protection of human research subjects at 45 CFR 46.116(a)(1): a complete description of the procedures to be followed, and identification of any procedures which are experimental.  
OHRP notes there was a single institutional review board (IRB)-approved protocol, "Computerized Training for Anxiety Disorders" that used one main informed consent document.  We have determined that the informed consent document for the study "Computerized Training for Anxiety Disorders" does not adequately provide a complete description of the research procedures, as required by HHS regulations at 45 CFR 46.116(a)(1).  SDSU acknowledged this noncompliance in correspondence with our office.  

a) The complainant alleged and we determine that the informed consent document does not include a complete description of all of the procedures that a prospective subject must undergo to determine eligibility, including completion of a demographic questionnaire, rating of the emotionality of words in a word list, and participation in a diagnostic interview.
Corrective Action:  SDSU has asked Dr. Amir to submit to the IRB for review the telephone screening script he and his research associates use, which more accurately conveys the content of the screening tool, and has asked him to include an indication of the length of time the screening will likely take, and the voluntary nature of answering any questions during the screening.  SDSU has asked Dr. Amir to remove the questions on the screening tool which ask for identifying information, and to have those specific questions be on a separate sheet of paper which can be uncoupled from the rest of the screening information in the event that the screening information needs to be kept (see allegation A(5) which follows). The name of the potential participant will be replaced with a code, with the code and identifying information match kept on a password protected computer database, similar to the data spreadsheets currently kept as part of this project.  

Required Action:  By November 24, 2015 please provide a revised, IRB-approved informed consent document with a description of the procedures used to determine subject eligibility.

b) The complainant alleged and we determine that the informed consent document for this study does not accurately describe where the study activities will take place.  The consent states "All portions [of the study] will be conducted at the Anxiety Disorders Clinic at SDSU." However, some portions of the study are completed at home by the subjects. Additionally, the name of the clinic is the Center for Understanding and Treating Anxiety, not the Anxiety Disorders Clinic.  

Corrective Action:  SDSU has asked Dr. Amir to change the wording to “The majority of the study will be conducted at the Center” and has asked him to ensure consistency across his written materials regarding the name of his facility. These corrective actions adequately address the determination and are appropriate under your assurance.

Recommended Action:  We recommend that the consent form indicate that some aspects of the study will or may be conducted at the subject’s home.  

c) The complainant alleged and we determine that the informed consent document for this study does not accurately describe compensation for the study.  The consent document states "Incentives to Participate: Students: Students will receive one experimental psychology credit per hour of participation . . . Students may opt to receive $10 instead of one credit per hour of participation.'' However, only students who have fulfilled their required number of hours have the option of receiving monetary compensation, and so it is not true that students may opt to receive monetary compensation instead of credit hours.

Corrective Action:  SDSU has asked Dr. Amir to specifically state that the compensation would only be available once the subjects have exhausted their research credit hours. The wording of the consent form has been changed to: “Students will receive one experimental psychology credit per hour of participation. You may fulfill your psychology research participation requirement and receive your credit by doing an alternative assignment that does not involve participation in research but involves comparable effort and duration to research participation. Students who have completed their research credit hour requirement and are eligible to participate may receive the same compensation as others enrolled in the study, $10 for every hour of participation.”  These corrective actions adequately address the determination and are appropriate under your assurance.

2) The complainant alleged that subjects in this study were provided a copy of the consent form only if they requested one, in contravention of HHS regulations at 45 CFR 46.117(a), which require provision of a copy of the informed consent document to the subject or the subject’s legally authorized representative.  

Based on the documentation provided in your October 24, 2014 correspondence, we determine that this allegation of noncompliance is unproven.  Your response indicated that Dr. Amir reports that he provides to all participants a choice of either a paper copy of the consent form, or a slip of paper with a link to an electronic version of the consent form on the lab web page. The large majority of participants do not retain their paper copy of the consent after completing the consenting process, and instead opt for the link provided. Dr. Amir and his staff provide a box by each exit to the lab where participants can leave their paper copy of the consent upon exiting to recycle these paper copies; he also has boxes with extra copies of the consent forms, and participants are free to take as many copies of the consent form as they wish. The location of this box and the copies in it has been confirmed.

3) The complainant alleged that changes to the research were made without prior IRB review and approval, in contravention of HHS regulations at 45 CFR 46.103(b)(4)(iii).  We note the following:
a) The complainant alleged that the first 20 subjects in the study were not randomized nor were clinicians blind to the intervention assignment, in contravention of the grant application.  Your October 24, 2014 response indicated that Dr. Amir and his colleagues conducted a pilot open trial, where all the subjects were in the active group, and not randomized. January 21, 2015 correspondence from SDSU stated, “Dr. Amir notes that he had a brief conversation with one of our analysts at the time to ask about examining the efficacy of the intervention in an open trial; his memory is that he was verbally approved to do that, though he never submitted a modification to his approved protocol for that deviation [from random assignment to one of two conditions to actively assigning to one condition]. There is no documentation in our records of that conversation, nor is the analyst in question here any longer. In short, while Dr. Amir believes he had approval to move forward, there is no existing documentation to indicate knowledge of or approval for that open trial.”
b) The research utilized a screening tool and a screening script for students who called expressing interest in the study to determine their eligibility for the study.  Your response indicated that this screening tool has not been reviewed in Dr. Amir’s reports of progress since a more generic screening tool was initially approved in 2007, nor had the screening script ever been reviewed until you investigated the allegations we presented in our September 12, 2014 letter.  
We determine that the investigator implemented these changes to the research without prior IRB review and approval, in contravention of HHS regulations at 45 CFR 46.103(b)(4)(iii).  
Corrective Action: The IRB has now reviewed and approved the revised screening tool and the screening script.   In addition, SDSU has implemented a checklist for use by the members of the Institutional Review Board as they read through protocols which they have been assigned to review so that the reviewers will be aware of all materials they should be reviewing in order to make an appropriate review and approval determination.

Required Action: Please provide OHRP by November 24, 2015 with a corrective action to address the above determination that changes to the research were made without prior IRB review and approval, in contravention of HHS regulations at 45 CFR 46.103(b)(4)(iii). In your corrective action, please indicate how SDSU will help ensure that investigators do not implement changes to research without prior IRB review and approval, except when necessary to eliminate apparent immediate hazards to the subject.

4) We determine that the following allegations of the complainant regarding informed consent are unproven:
a) The complainant alleged that only participants with (generalized) anxiety are entered into the GAD study (or for the social phobia studies, those with clinical levels of social phobia) and that non-anxious individuals do not qualify for the study, but the informed consent document states "Participants will be individuals with and without anxiety."

Based on the documentation provided in your October 24, 2014 correspondence, we have determined that the allegation of noncompliance is unproven.  The current approved consent form being used for Dr. Amir’s studies pertains to all of his studies which assess and modify cognitive biases in individuals with normative and pathological anxiety including obsessive-compulsive disorder (OCD), social phobia (SP), generalized anxiety disorder (GAD), and panic disorder (PD). Various modifications of the protocol, with supplemental consent forms, have extended this research to those with anxiety and eating disorders. Both the approved protocol and consent form cover the study of etiological factors (i.e. cognitive, self -report, brain imaging, and psycho-physiological measures) in anxious individuals (e.g., individuals with social anxiety, generalized anxiety, OCD, or panic disorder) as compared to each other and as compared to non-anxious controls, and so some of the participants do not have anxiety.

b) The complainant alleged that the consent form divides the study description into four parts for the subjects: Parts 1 through 3 largely describe the time sequence, tasks, and procedures used during the social phobia studies, not the GAD study. The complainant alleged that this section of the consent form also refers to random assignment to one of two groups, one of which receives the anxiety treatments and the other of which receives the non-treatment (placebo).  The complainant alleged that the GAD study uses a completely different time course, and participants are randomly assigned to one of four groups, three of which receive some form of active treatment, with the fourth group receiving clinical monitoring.  

Based on the documentation provided in your October 24, 2014 correspondence, we have determined that the allegation of noncompliance is unproven.  Your response indicated that for all treatment studies examining the efficacy of computerized treatments for anxiety, there is assessment of symptoms by self- report and through interview measures; assessment of cognitive symptoms through response latencies and accuracy in identifying words, sentences, and pictures; and psycho-physiological measures (e.g., ERN, LPP). Participants then complete the computerized intervention and then again complete the same assessments. Therefore, the time sequence is the same across all studies. Moreover, all treatment studies follow the procedures of a randomized control trial and include an active arm and a control arm. This information is conveyed to the participant in the consent form.  It is true that in the GAD study, Dr. Amir is examining the sequencing of the treatment in the active arm. However, all individuals in the active group receive the exact same treatment components though in different sequence (attention modification followed by applied relaxation; applied relaxation followed by attention modification; both simultaneously). As there are no distinctions between the various subgroups of the active group in terms of the active treatment component they receive, all studies are described as having an active arm and a control arm.

c) The complainant alleged that the informed consent document for these studies states "Part 4 . . . Behavioral assessments and physiological measure may also be taken. Heart rate, skin conductance, and EEG measurements will be taken."  However, the complainant alleged that heart rate, skin conductance, and EEG measurements are not taken for the studies on Social Phobia.  

Based on the documentation provided in your October 24, 2014 correspondence, we have determined that the allegation of noncompliance is unproven.  Your response indicated that not all participants are eligible for all of the assessments for various reasons (e.g., they may have skin allergies to the gel used for EEG), and some participants who are eligible nevertheless opt out of some assessments, and that subjects may participate in the research even if not all assessments are carried out. Further, the consent form clearly states that "You may be asked to participate in one or more portions of the study" under the study description.

d) The complainant alleged that the informed consent document for these studies states "Incentives to Participate ... Clients. You will be paid at a rate of $10 per hour for the number of hours you have participated."   The complainant alleged that the subjects for the study are not paid by the hour; instead, they are paid $80 upon completion of their in-lab tasks at pre-, mid-, and post-study.  

Based on the documentation provided in your October 24, 2014 correspondence, we have determined that the allegation of noncompliance is unproven.  Your response indicated that over the years-long course of these studies, Dr. Amir and his team have conducted multiple assessments; overall, the length of time for these assessments is roughly 8 hours. Therefore, participants are verbally informed that their compensation will be $10 per hour or about $80 for each assessment. However, SDSU has asked Dr. Amir to amend his consent form to state: “You will be paid at a rate of $10 per hour for the number of hours you have participated. For example, if each assessment takes approximately 8 hours to complete, your payment would be $80 for each assessment. You will be paid $10 an hour for each hour you participate even if you do not finish the assessment.”

5) The complainant alleged that the informed consent document for these studies states "If you are not eligible to participate, the information obtained from you during screening will be omitted from this study and shredded to protect your privacy.”  The complainant also alleged that the information regarding prospective subjects who are found not to be eligible is retained--not shredded-- in file cabinet B, 4th drawer.  
Based on the documentation provided in your October 24, 2014 correspondence, we make no finding regarding the allegation.  Despite the statement quoted above, some ineligible subjects were informed that information about them would be kept temporarily.  Your response indicated that a small subset of screening instruments is in fact kept in specific circumstances and in each instance, the participant is informed of these circumstances, and these materials are kept in a locked file cabinet, and never for longer than three months. It is not clear to us if any of the information obtained in these circumstances is from subjects who were not eligible.  

B. Questions and concerns

1) [Redacted]

2) [Redacted]

[Redacted]

[Redacted]

3) [Redacted]

4) [Redacted]

[Redacted]

5) [Redacted]

C. Resolved concerns

The following concerns we expressed in our September 12, 2014 letter have been adequately addressed by SDSU.
We expressed concern that certain changes to the research may have made without prior IRB review and approval, in contravention of HHS regulations at 45 CFR 46.103(b)(4)(iii).  Based on some of the complainant’s allegations, we were concerned that the IRB reviewed and approved these alleged changes before they were implemented: The participant compensation plan detailed in the GAD grant has been altered; and the grant states that “Group assignment will occur on a stratified random basis by using the minimization method” but, no such stratification is taking place.

Institution Response:  You indicated that the subjects are indeed stratified and
randomized, and the randomization is further checked after each 25 subjects are assigned and complete the post assessment. Drs. Plemmons and Prislin examined Dr. Amir’s database for the past several years and found this to be accurate.  Changes to the subject compensation were reviewed and approved by the IRB.

Based on your response, we find no regulatory violations relating to our expressed concern.

D. Recommendations

We make the following recommendation regarding the consent document for this study:
We note that the current informed consent document states: “300 participants will be recruited for this study.”  However, the IRB approved a modification to recruit 1500 subjects.  We recommend that the informed consent documents be modified to note this.
Please provide us with responses to the above required actions, questions and concerns by November 24, 2015.  Feel free to contact me if you would like guidance in developing a corrective action plan.

We appreciate your institution’s continued commitment to the protection of human research subjects.  

Sincerely,

Kristina C. Borror, Ph.D.
Director, Division of Compliance Oversight

cc:
Mr. Rick Gulizia, Director, Division of Research Affairs, SDSU
Dr. Ramona Perez, Chairperson, IRB/Professor, SDSU
Dr. Amir Nader, SDSU

Dr. Joanne Less, FDA
Dr. Thomas Insel, Director, National Institute of Mental Health, National Institutes of Health (NIH)
Dr. Sherry Mills, NIH
Dr. Michelle Bulls, Director of OPERA, Office of Extramural Research, NIH
Ms. Sarah Carr, Office of Science Policy, NIH