February 2, 2016 - San Diego State University

Dear Dr. Welter:

Thank you for your November 23, 2015 report in response to our October 13, 2015 letter regarding allegations of noncompliance with Department of Health and Human Services (HHS) regulations for the protection of human research subjects (45 CFR part 46) in research at San Diego State University (SDSU).  In our October 13, 2015 letter, we made the following determinations, among others:

A. Determinations made October 13, 2015 regarding the above-referenced research

1)  The complainant alleged and we determined that the informed consent document did not include a complete description of the procedures to be followed, and identification of any procedures which are experimental as required by HHS regulations for the protection of human research subjects at 45 CFR 46.116(a)(1). We determined that the consent document did 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, did not accurately describe where the study activities will take place, and did not accurately describe compensation for the study.

Corrective Actions:  In addition to the corrective actions taken by SDSU outlined in our October 13, 2015 determination letter, the informed consent document, telephone screening script, and confidentiality protections have been revised, and the revised documents were reviewed and approved at the November 17, 2015 meeting of the convened IRB.

2) The complainant alleged and we determined that the following changes to the research were made without prior IRB review and approval, contrary to HHS regulations at 45 CFR 46.103(b)(4)(iii):

a) Dr. Amir and his colleagues conducted a pilot open trial, where all the subjects were in the active group, and not randomized. While Dr. Amir believed he had approval to move forward, there is no existing documentation to indicate that the IRB had knowledge of or provided 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.  This screening tool had 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.  
 

Corrective Action: In addition to the corrective actions taken by SDSU outlined in our October 13, 2015 determination letter, SDSU has made the following corrective actions to 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: The principal investigator and study team members for this specific protocol attended a mandatory re-training that emphasized the proper procedures and regulatory requirements for making changes to approved IRB protocols; the principal investigator has implemented a system in his office whereby all study related correspondence between the study team and the IRB is logged in thus avoiding the implementation of revised study procedures without prior IRB approval; a more clear guidance document has been developed and posted on the SDSU HRPP website titled "Human Research Program: Standards and Practices” including the requirement to obtain IRB approval prior to making changes to an already approved research protocol; a more robust training platform is being utilized that contains detailed content regarding regulatory requirements for conducting human subjects' research and is now mandatory for all faculty, staff and students involved in human subjects' research; more than 35 IRB workshops, presentations and guest lectures (in research methods classes) have been given to increase awareness campus- wide regarding federal and university policies and investigator responsibilities for the protection of human subjects; the SDSU HRPP website was updated containing better educational materials; three new Certified IRB professionals were hired to assist faculty, staff and students in the conduct of human subjects' research; open office hours have been established whereby IRB analysts will be available for consultation, guidance and advice for faculty, staff and students involved in human subjects' research.

B. Additional determinations regarding the above-referenced research

1) We note that an advertisement approved by the IRB for this study indicated that confidential help is available for participants’ shyness and they may be eligible to receive free treatment.  In addition, the response people were given when they contacted the researchers was the following:
Hi,
This is XXXXXXX, a research assistant at the SDSU Anxiety Clinic.  Thanks for your interest in our program.  We currently have two experimental computerized treatments available free of charge. . . .

Your November 23, 2015 response clarified that the “free treatment” offered in the advertisement and email is referring to the research intervention.  We have determined that this information is not consistent with the regulatory requirements at 45 CFR 46.116(a)(3), which requires that informed consent include description of any benefits to the subject or to others which may reasonably be expected from the research.  We have determined that these statements may overpromise or give a false impression of the likelihood of benefit.  

Corrective Action: The PI has modified the benefits section of the informed consent form to read: "Study treatment is a possible benefit; however, the PI cannot guarantee you will benefit from the study treatment." The revised consent form was reviewed and approved at the November 17, 2015 meeting of the convened IRB.
2) We have determined that the IRB approved the above-referenced research contingent upon substantive modifications or stipulations that were directly relevant to the determinations required by the IRB under HHS regulations at 45 CFR 46.111 without requiring additional review by the convened IRB. The following stipulations (among others) were noted:
 

a) Clarify what will be done with data for participants who are determined not to be eligible.
b) It is not clear how the psychology subject pool will be used for recruitment purposes.
c) Although not deliberate in the research design, the possibility for subtle coercion exists when the potential subjects are in a subservient position to the investigator (e.g., employee, patient, etc.) . . . .
d) Discuss the recruitment procedure for those recruited from the SDSU anxiety clinic as well as for those recruited from other clinics and the community . . . .
e) Clarify if participants will undergo the attention and interpretation training individually or in groups.
f) Discuss whether attention and interpretation sessions will take place concurrently (in a single visit) for those participants assigned to both treatment conditions.
g) The protocol notes a variety of physiological indicators that will be assessed (i.e., EEG, heart rate, and skin conductance). However, the procedure that is described appears to be for EEG measurement only. Clarify the nature of additional physiological measurements, equipment to be used, and any risks for physical discomfort. Include this information within the protocol and consent form.
h) The number of assessment instruments included is very large and appears to be somewhat redundant. Discuss the rationale for including multiple measures of each outcome target. In addition, it is unclear whether the entire SCID will be administered, or if only specific segments will be included. Likewise, it is unclear whether lifetime or only current diagnoses will be assessed. Explain how the SCID will be administered.
i) Provide details regarding the system that will be implemented for patients who may present with significant psychological distress, or suicidal intent, and may require crisis intervention (i.e., or hospitalization).
j) Clarify the total incentive amount that may be awarded and explain how it will be paid (i.e., increments per activity/therapy session) . . . .

We also note that at the September 17, 2013 IRB meeting a modification involving Transcranial Direct-Current Stimulation (tDCS) was approved.  The IRB requested more information in general about tDCS, and requested the following additional information (among other things ): “Briefly describe how testing subjects using Transcranial Direct-Current Stimulation (tDCS) is consistent with the original purpose of this protocol . . . Briefly describe the benefits of Transcranial Direct-Current Stimulation (tDCS) testing in normal healthy subjects . . . .”  However, the IRB approved the modification without this information.
We have determined that the IRB would have needed the information described in the preceding paragraph and the list of stipulations above in order to meet the regulatory requirements at 45 CFR 46.111, which require that in order to approve research covered by this policy the IRB shall determine that the following requirements are satisfied (among others):  risks to subjects are minimized; risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result; informed consent will be sought from each prospective subject or the subject's legally authorized representative, in accordance with, and to the extent required by §46.116.  Your response indicated that a subcommittee, including the IRB chairperson and other IRB members, convened to discuss the PI's response. The subcommittee subsequently approved the modification. However, this is inadequate as the research was not eligible for expedited review and must be approved at a convened meeting of the full IRB.
 

Corrective Action: The practice of forming a subcommittee to review principal investigator responses has been eliminated. Currently all principal investigator responses to tabled (deferred) protocols are reviewed at a fully convened meeting. We recommend that SDSU review the OHRP guidance on IRB Approval of Research with Conditions at http://www.hhs.gov/ohrp/policy/conditionalapproval2010.html for help in determining when a study may be approved when the IRB has stipulations or conditions and when the study must come back to the convened IRB for approval.

3) After we opened our investigation, you discovered that the telephone screening script had never been approved by the IRB. The IRB subsequently approved the script.  We previously expressed concern that the telephone screening consent script did not appear to include the following required elements of informed consent:
a. Section 46.116(a)(2): A description of any reasonably foreseeable risks and discomforts.
b. Section 46.116(a)(5): A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained.
c. Section 46.116(a)(7): An explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights, and whom to contact in the event of a research-related injury to the subject.
d. Section 46.116(a)(8): A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

HHS regulations at 45 CFR 46.116(a) require that when seeking informed consent specific information shall be provided to each subject unless the IRB approves a consent procedure which does not include, or which alters, some or all of the required basic elements of informed consent provided in accordance with 45 CFR 46.116 (c) or (d).  We have determined that the informed consent documents reviewed and approved by the IRB for the above-referenced study failed to include those basic elements required by HHS regulations at 45 CFR 46.116(a).

Corrective Action: The principal investigator has modified his phone screening to include a statement that all information obtained from ineligible participants is shredded. A revised phone screening document with all the requested changes was submitted to the IRB on October 23, 2015. The updated phone screen and request to waive documentation of consent were reviewed and approved by the convened IRB at the November 17, 2015 meeting.

4) We note that the June 18, 2014 IRB-approved protocol for protocol #3715 states:

“Confidentiality Procedures

All participants are assigned a 12 digit number at the beginning of the study. All data will be coded based on that number. A list of names and numbers will be kept in a locked file cabinet in the lab.”

Similarly, the consent document states “All of the information you provide will be associated with a number and data will be recorded based on that number.”

However, your October 24, 2014 response stated:  “However, for active participants, as the various studies involve multiple visits to the lab, as well as follow ups over the course of up to one year, the consent form and identifying information are kept in the participant’s folder until the participant reaches the end of the study.”  It appears that subject identifying information is kept with subject data in contravention of the consent form statement.
HHS regulations at 45 CFR 46.116(a) require that when seeking informed consent specific information shall be provided to each subject unless the IRB approves a consent procedure which does not include, or which alters, some or all of the required basic elements of informed consent provided in accordance with 45 CFR 46.116 (c) or (d).  We have determined that the informed consent documents reviewed and approved by the IRB  for the above-referenced study failed to adequately address the following basic element required by HHS regulations at 45 CFR 46.116(a)(5):  a statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained.  

Corrective Action: The confidentiality section of the consent form has been modified to state: "Data will be kept confidential to the extent allowed by law. All confidential study data will be kept in a locked file cabinet." The revised consent form was reviewed and approved at the meeting of the fully convened IRB on November l 7, 2015.

All of the corrective actions identified above in sections A & B adequately address the determinations.  At this time, there should be no need for further involvement by our office in this matter.  Please notify us if you identify new information which might alter this determination.

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
1101 Wootton Parkway, Suite 200
Rockville, Maryland 20852
Telephone: 240-453-8132
FAX: 240-453-6909
E-mail: [email protected]

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. Bruce Cuthbert, Acting Director, National Institute of Mental Health, National Institutes of Health (NIH)
Dr. Sherry Rodgers, Director Office of Extramural Programs, NIH
Dr. Michelle Bulls, Director of OPERA, Office of Extramural Research, NIH
Ms. Sarah Carr, Office of Science Policy, NIH