Investigator Handbook
Chapter 10: OTHER CONSIDERATIONS

Medical Record Review for Research Purposes

All retrospective medical record reviews conducted at LBJ Hospital, Harris County Psychiatric Hospital, Thomas Street Clinic, or at a hospital within the Memorial Hermann Healthcare System, for the purposes of research must be approved by the CPHS. This may be accomplished by submitting a request through the iRIS system, which will be reviewed and approved administratively. 

Retrospective medical chart reviews also require approval by the Memorial Hermann Research Office when using Memorial Hermann Hospital or one of the MHHS community hospitals. Please contact the Memorial Hermann Hospital Center for Clinical Innovation and Research at (713) 704-4256 for further information. If you expect to use the electronic medial record at the Memorial Hermann Hospital, call their Information System Support Center at (713) 448-5370 to request a sign-on form.

Your request to the CPHS must contain the following information:

• the scientific question
• the rationale
• an estimate of the number of records to be reviewed and the time period to be covered
• the names of the persons conducting the reviews if other than yourself

Of particular importance:

• If you will be abstracting patient personal identifiers (i.e., names, hospital numbers, social security numbers, etc.), indicate how confidentiality will be maintained (e.g., coded lists to be maintained by and available only to the PI, etc.).  Also indicate if you will not be abstracting such identifiers.

• If it is necessary to contact the patient for purposes of follow-up, report this to the CPHS, and you will be advised of the appropriate mechanisms.

Guidelines for Blood Draws in Pediatric Populations

In any 24-hour period, phlebotomy for research studies in infants and children should not exceed 5% of the total blood volume and ideally should be less than 3% of the total blood volume.

In any one-month period, phlebotomy for research studies in infants and children should not exceed 10% of the total blood volume.

Inernational Research

UT-Houston investigators conducting international research must adhere to the same high standards of research ethics required for human subjects research conducted in the U.S. while at the same time being sensitive to local cultures and practices (HRP PP IV.16 Research Conducted at International Sites http://www.uth.tmc.edu/orsc/policies/IV.16.htm).  CPHS considerations/requirements for this research are dependent upon the role of the foreign institution/site in the research.

Research Where Foreign Site Is Actively Involved in Research
If the foreign site/institution is actively involved in the proposed research, additional requirements beyond those for domestic research include the following.  

1. The foreign site must file an assurance of compliance with OHRP.
2. The foreign site must have procedures that provide protections at least equivalent to those in 45 CFR 46.
3. The CPHS must have a copy of the foreign site’s Research Ethics Board (REB)/Independent Ethics Committee’s review/approval of the study.

Research Where Foreign Site Is Not Actively Involved in Research
If the foreign site/institution is not actively involved in the proposed research, additional requirements beyond those for domestic research include the following.  

• The CPHS must have a copy of the foreign site’s REB’s (1) review/approval of the study or (2) documentation that approval is not required. If the site does not have an REB, the PI must submit a letter of cooperation that documents appropriate institutional officials have approved the proposed research.
• The PI and foreign site must notify the CPHS if the role of the foreign site changes.

Research Conflicts of Interest

Research related financial interests of investigators or the institutions create potential conflicts of interest that may bias the design, conduct or reporting of research; jeopardize the protection of human research subjects; detract from employees’ teaching, research, clinical or administrative responsibilities; inappropriately influence the research training of students or fellows; or result in improper transfers of state resources to research sponsors or licensees.  The Institution therefore requires investigators to disclose significant research related financial interests1 (HOOP 23.10 Research Conflicts of Interest).  Disclosures are reviewed by UTHSC-H’s Research Conflicts of Interest Committee, and it assesses if the potential conflicts can/should be managed, reduced, or eliminated in order for the research to be approved.  When reviewing significant financial interests in human subjects research, the Committee applies a rebuttable presumption standard (i.e., individuals with significant financial interests may not conduct the research unless there are compelling circumstances). Compelling circumstances include factors such as unique investigator expertise; unique institutional resources; unique access to particular patient populations; nature of science; level of risk for human subjects; and degree to which financial interests and research are linked

The Research Conflicts of Interest Committee forwards its recommendations to the Executive Vice President for Research (EVPR) and, if the research involves human subjects, the CPHS.  The EVPR determines if potential conflicts can be appropriately managed by implementing a conflict of interest management plan, but the CPHS makes the ultimate determination as to whether a plan can appropriately protect human subjects (HRP PP VII.02 COI Disclosure by PI/Key Study Personnel http://www.uth.tmc.edu/orsc/policies/VII.2.htm).  Protocols that involve research where investigators have significant research related financial interests can not receive final CPHS review and approval until the CPHS reviews/considers the recommendations of the Research Conflicts of Interest Committee for addressing the financial interests.

Significant financial interest in research refers to anything of monetary value that would reasonably appear to be affected by the outcome of the proposed research, regardless of whether that entity is sponsoring the research. Such interests include, but are not limited to:

• Salary or other payments for services (e.g. consulting fees or honoraria) that have in the prior 12 months exceeded $10,000, or are expected to exceed that amount in the next 12 months from a single entity. This does not include salary or other remuneration from UTHSC-H or, as applicable, other academic institutions.
• Equity interests (e.g. stocks, stock options, or other ownership interests) that exceed $10,000 in value as determined through reference to public prices or other reasonable measures of fair market value or represent more than a 5% ownership interest in any single entity. This does not include interest in mutual funds where the individual has no control over the selection of holdings.
• Any equity interests in a non-publicly traded for-profit financially interested entity.
• Intellectual property rights (e.g. patents, patents in which the investigator has a financial interest, copyrights, and royalties from such rights).
• Payments or entitlements paid by the sponsor in connection with the research, including bonus or milestone payments, that are not directly related to the reasonable costs of the research.
• Service as an officer, director, or fiduciary for a financially interested company.

In addition to the exceptions noted above, the term significant financial interest in research does not include:

• Income from seminars, lectures, or teaching engagements sponsored by public or nonprofit entities.
• Income from service on advisory committees or review panels for public or nonprofit entities.

Investigators should also disclose other significant financial interests not specifically required by the Policy if they have concerns the interests would reasonably appear to be affected by the proposed research (e.g. significant financial interests of family members other than a spouse or dependent children).

Compliance and Auditing

Clinical research non-compliance is conducting research involving human subjects in a manner that disregards or violates federal and institutional regulations governing such research. This may include, but is not limited to, inadequate or non-existent procedures for informed consent, inadequate supervision of research involving drugs, devices or procedures, failure to follow recommendations made by the IRB to insure the safety of subjects, failure to report adverse events or proposed protocol changes to the IRB, and failure to provide ongoing progress reports.
The CPHS may audit studies involving human subjects to assess compliance with human subjects research regulations/requirements and assure subjects rights are protected (HRP PP III.01 Compliance Oversight http://www.uth.tmc.edu/orsc/policies/III.1.htm).  These reviews may include the following. 

Routine compliance reviews
Clinical research monitors from the Office of Research Support Committees review representative samples of greater than minimal risk protocols as part of a general compliance program.  These reviews are coordinated with the PI, and may include: reviews of recruitment materials and informed consent documents; interviews with study personnel; observation of study activities; budgeting and billing compliance monitoring; and storage/use of investigational drugs/devices. Results are reported to PIs and the CPHS, and PIs respond to any findings and recommendations via iRIS.

For-cause audits
For-cause audits may be initiated by the CPHS or Executive Chair at any time during a study or after study closure.  For-cause audits frequently are used for studies with higher levels of risk (e.g. vulnerable populations, gene transfer, international research, waivers of informed consent, phase I studies).  The reviews are conducted by clinical research monitors from the ORSC and are coordinated through the PI.  Results are reported to PIs and the CPHS, and PIs respond to any findings and recommendations via iRIS.

Findings of non-compliance and processing allegations
The CPHS shall respond to all reports of alleged non-compliance. These reports may come from a variety of sources to the CPHS that include the Office of Legal Affairs, via the UTHSC-H Hotline; a report of findings from the Clinical Research Monitor; a subject or family member of a subject in a research project, or the principal investigator’s report of an adverse event, unanticipated problem, or protocol deviation.

Inquiry
Whenever an allegation or complaint of non-compliance is made, the Director will expeditiously bring it to the attention of the Executive Committee. An ad hoc Inquiry Panel will be established. The Director will also send written notice of the allegations to the researcher within 10 working days. If the complaint raises issues of safety and welfare for research subject that are apparent from initial review, the Director also will give the researcher notice of an opportunity to address in his/her response the impact of the immediate suspension of the project(s).

The Executive Chairperson shall request an inquiry to determine if there is substance to the allegation.  In the inquiry phase, factual information is gathered and expeditiously reviewed to determine if an investigation of the complaint is warranted. An inquiry is not a formal hearing or an in depth analysis of the allegation; it is designed to separate allegations deserving further investigation from those that are frivolous, unjustified or related to minor infractions or misunderstandings.

The Inquiry Panel will review the allegation of non-compliance, the response from the researcher, and any other information necessary to determine whether an investigation is warranted. The Inquiry Panel may interview the researcher and others, but is not obligated to do so. It may be necessary to secure critical data or materials at the outset of the inquiry to protect the integrity of those data. The IRB maintains the authority to secure such materials at any time during an inquiry or investigation.

The inquiry report will be submitted to the Executive Committee, who determines if there are sufficient findings to warrant an investigation. 

Investigation
The purpose of the investigation is to explore the allegations by assembling and examining relevant information. The Investigation Panel's charge is to generate a report that summarizes the information considered, conclusions regarding as to whether there was non-compliance with regulations, and recommendations for action. During an investigation, additional information may emerge that justifies broadening the scope beyond the initial allegations. If an investigation is warranted, the PI will be notified in writing that an investigation has been initiated and  the PI shall be informed if new and different allegations are discovered during the course of the investigation.
An ad hoc subcommittee of at least 3 members of the CPHS will conduct the investigation. These members will have areas of expertise suited to reviewing the complaint. Depending on the nature and scope of the complaint, CPHS members may be relieved of their regular IRB duties during the investigation.

The Investigation Panel may use any and all materials and reports gathered during the inquiry phase but are not limited to actions or conclusions of the Inquiry Panel. The Investigation Panel may obtain documents and other records relevant to the investigation (e.g. researcher's records, medical charts, grant applications, etc.). The Panel may interview any persons who may have information relevant to the complaint. The Panel may draw on the resources of the institution or external consultants to assist in the review of issues that require expertise beyond or in addition to that available on the Panel.

The PI under investigation will be given an opportunity to submit written comments and to appear before the Panel on at least one occasion prior to the Panel issuing its report. The PI may offer relevant information to the Panel and suggest other individuals to be interviewed. An attorney may also accompany the PI at any time he/she appears before the Panel. The PI shall give the Panel notice of the attorney's participation at least 48 hours prior to any interview.

At the conclusion of its investigation, the Investigation Panel will prepare a report summarizing the information it has considered and outlining its conclusion and recommended actions. A copy will be sent to the PI who will be given 10 working days in which to submit comments. The Panel will review any such comments and decide whether to modify the preliminary report. When completed, the Investigation Panel will distribute its report as appropriate. The investigation phase is expected to be completed within 60 working days with an extension possible if warranted.

Outcome
The Executive Committee will base its decision on the report of the Investigation Panel. Appropriate actions to be taken include but are not limited to:

• Dismissal of the complaint as unjustified
• Remediation or educational measures
• Increased reporting by the PI of human subject research activity
• Restrictions on research practice (e.g. limiting privileges to minimal risk/supervised projects)
• Suspension of approval for one or more of the PI's studies
• Termination of approval for one or more of the PI's studies
• Referral to other University officials or committees for possible action by those bodies.

FDA Inspections

The FDA has GCP regulations governing the approval, conduct, review and reporting of clinical research intended for submission to the FDA,1 and it monitors compliance with these regulations through routine and directed (for cause) inspections.

• Routine inspections are assigned for clinical drug studies conducted under New Drug Applications (NDAs) and device studies conducted under Pre Market Approvals (PMAs).

• Directed or “for cause” inspections are conducted for several reasons. Some of the reasons that may trigger an audit include problems that are identified during the review process and/or complaints received by the FDA.  These complaints may come from the sponsor, the local IRB or institution, subjects, the public, or other agencies.

UTHSC-H PIs preparing for FDA inspections should follow steps outlined in UTHSC-H documents (1) the FDA Audit Checklist and (2) Actions for an FDA Inspection.  These documents can be found on the following three UTHSC-H websites:

http://www.uth.tmc.edu/orsc/
http://www.uth.tmc.edu/research/
http://legal.hsc.uth.tmc.edu/icompliance.html

1     21 CFR 312:  IND regulations (rev.1987), 21 CFR 50:  Informed consent (rev.1981), 21 CFR 56:  IRB (rev.1981), 21 CFR 314:  NDA regulations (rev. 1985)

Responding to Research Subjects' Complaints or Requests for Information

Investigators should respond promptly to research subject’s questions and concerns.  The consent form should always include (1) a number where study staff can be contacted 24/7, and (2) the number for the CPHS (713-500-7942) for subjects who might require a neutral party for additional information or to register complaints.  Subjects can also email questions/concerns to the CPHS at cphs@uth.tmc.edu or report concerns to the UTHSC-H Compliance Hotline (1-888-472-9868 or compliance@uth.tmc.edu).

Classroom Projects

UTHSC-H classroom projects need not be reviewed by the CPHS if:

• the project is not research
• the results will not be distributed outside the classroom or institutional setting, or
• the projects are used to evaluate or review a program in order to build a better program.

If, however, the results of the project will be published or otherwise distributed, it must be reviewed by the CPHS.

If in doubt, it is wise to submit the project for review.