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 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.

1. 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.
   
2. 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. Protocols that involve research where investigators have significant research related financial interests cannot 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.

1 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).

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

Certificate of Confidentiality

A Certificate of Confidentiality should be obtained for a research study when subjects’ participation, if it became known outside of the research, could place subjects at risk of criminal or civil liability or be damaging to their financial standing, health care, insurability, employment, employability or reputation. Certificates of Confidentiality help to minimize risks to subjects by adding an additional level of protection for maintaining confidentiality of private information.

Certificates of Confidentiality are issued by the National Institutes of Health (NIH) and other HHS agencies to protect identifiable research information from forced or compelled disclosure. They allow the investigator and others who have access to research records to refuse to disclose identifying information on research participants in civil, criminal, administrative, legislative, or other proceedings, whether federal, state, or local. Certificates of Confidentiality may be granted for studies collecting information that, if disclosed, could have adverse consequences for subjects, such as damage to their financial standing, employability, insurability, or reputation. By protecting researchers and institutions from being compelled to disclose information that would identify research subjects,

Certificates of Confidentiality protect subjects from compelled disclosure of identifying information but do not prevent the voluntary disclosure of identifying characteristics of research subjects. Researchers, therefore, are not prevented from voluntarily disclosing certain information about research subjects, such as evidence of child abuse or a subject's threatened violence to self or others.

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. 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.

Noncompliance
Compliance: Adherence to all research related requirements, good clinical practice requirements, CPHS requirements and applicable regulatory requirements.

Noncompliance: Noncompliance is a failure by an investigator to abide by research related requirements, good clinical practice requirements, CPHS requirements and applicable regulatory requirements. Some examples of noncompliance include, but are not limited to:

• Failure to obtain approval for research prior to initiating the research activities,
  
• Continuing research activities beyond the expiration date without obtaining continuing review approval,
  
• Failure to obtain informed consent when required,
  
• Failure to file an adverse event report,
  
• Implementing changes to the protocol without prior approval,
  
• Performance of research at an unapproved site, or
  
• Failure to adhere to the approved protocol.

Serious Noncompliance: An act or omission to act that has the potential to increase a physical, psychological, safety, or privacy risk to research participants.

Continuing Noncompliance: A repeated pattern, act, or omission to act that suggests a future likelihood of reoccurrence of the noncompliance.

Reporting to CPHS – CPHS encourages reporting of noncompliance by the Principal Investigator (PI), members of the research team or others. When a report of noncompliance is made by someone other than the Principal Investigator, the confidentiality of the reporter will be maintained. Reporter names will not be disclosed to the individuals involved in the complaint, unless disclosure is required to reconcile the situation.

CPHS may receive an allegation or a report of noncompliance by many means that include, but are not limited to:

• Voluntary notification by the Principal Investigator,
  
• Principal Investigator not responding to ORSC or CPHS queries,
  
• Information given by other staff of the institution,
  
• Information given by other members of the research team,
  
• Monitoring reports,
  
• Audit reports, or
  
• Complaints from research subjects.

Review by CPHS – Upon receipt of the allegation of noncompliance, the ORSC Director will determine if the allegation is valid. In order to make the determination of validity, the ORSC Director may solicit additional information about the allegation from study team or requesting the review of the research by the Clinical Research Monitor.

If the allegation of noncompliance is not valid, the ORSC Director will document the allegation and determination. If the allegation of noncompliance is valid, the ORSC Director communicates this information to the Executive Chairperson. The Executive Chairperson determines if the noncompliance is serious or continuing. In order to make this determination, the Executive Chairperson may solicit additional information about the allegation from study team or requesting the review of the research by the Clinical Research Monitor.

If the noncompliance is not serious or continuing, the Executive Chairperson may take no action or may write to the Principal Investigator describing the concern and require the Principal Investigator to give an explanation and outline a corrective action to avoid repeating the noncompliance. If investigator’s reply is not satisfactory, this is handled as serious or continuing noncompliance.

If the noncompliance is serious or continuing, the Executive Chairperson includes the noncompliance for discussion at the next scheduled Executive Committee meeting or convenes an urgent Executive Committee meeting. Executive Committee may decide to take action based on existing information or initiate an investigation by a subcommittee composed of at least 3 members. If any of the members have any conflicting interests, the investigation will be reassigned to another member.

The purpose of the investigation is to explore the noncompliance by assembling and examining relevant information. The subcommittee's charge is to generate a report that summarizes the information considered, conclusions regarding the noncompliance, and recommendations for action. During an investigation, additional information may emerge that justifies broadening the scope beyond the initial allegations.

The subcommittee shall have access to prior records of CPHS activities and documents regarding the specific research on iRIS and Documentum Systems. They will also have access to the monitoring report, if applicable. The subcommittee may obtain documents and other records relevant to the investigation (e.g. researcher's records, medical charts, grant applications, etc.). The subcommittee may interview any persons who may have information relevant to the noncompliance. The subcommittee 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 subcommittee.

The Principal Investigator under investigation will be given an opportunity to submit written comments and to appear before the Executive Committee. At the conclusion of the investigation, the subcommittee will prepare a report summarizing the information it has considered and outlining its conclusion and recommended actions. The subcommittee will submit the report to the Executive Committee. The Executive Chairperson or ORSC Director will write to the Principal Investigator outlining the concerns and request a response.

Outcome of CPHS Review: If the investigator offers a timely and satisfactory explanation for the concern, and Executive Committee accepts, the review process will be considered as completed and the Executive Chairperson will notify the investigator in writing that the research may continue and no further action is required. If the investigator offers an explanation that CPHS rejects, or if the investigator fails to respond within the specified time period, the Executive Committee may make a recommendation for further action that includes, but is not limited to:

• Request for more information before a final decision can be made;
  
• Request that the PI implement changes to the research protocol, procedures and/or informed consent documents;
  
• Request that the PI provide a corrective action plan to avoid a repeated occurrence in the future;
  
• Suspension or termination of CPHS approval for the study;
  
• Place the study on administrative hold;
  
• Review of one, some or all of the investigator’s research studies;
  
• Revision of the frequency of the continuing review process;
  
• Limitation of the types or numbers of studies for which an individual may serve as investigator;
  
• Required additional training of the PI and the research staff;
  
• Disqualification of the PI or member of the research staff from conducting research at UTHSC-H;
  
• Disallowance of research use of data collected;
  
• Notification of research participants regarding study problems (required when information may relate to the participants willingness to continue participation) or re-consent of participants;
  
• Notification of past participants of additional information;
  
• Recommendation to UTHSC-H Administration that further action be taken;
  
• Notification of complainant regarding decisions and/or outcome of the investigation.

Appeals

It is the policy of the UTHSC-H that research that has been disapproved by CPHS may not be conducted at UTHSC-H or by UTHSC-H staff. However, investigators may appeal decisions made by CPHS that are in contention, including CPHS decisions to disapprove, suspend, terminate, or stipulate modifications to submitted protocols and associated submission materials, including informed consent forms.

When CPHS disapproves, suspends, terminates, or stipulate modifications to submitted documentation, ORSC Staff will notify the investigator of the action and rationale of the decision by written correspondence. Within the official notification letter received by the investigator from CPHS, the investigator will be instructed to respond in writing to the decision.

If clarification of the written notice is needed, the investigator will be instructed to contact the ORSC staff for further clarification and instructions. Investigators who disagree with the decision of CPHS will be informed about the CPHS appeal process and available options for further consideration.

Submission of Appeal: When the investigator has decided to enter into an appeal process, the ORSC staff will instruct the investigator to provide the rationale and supporting information/material that will aid CPHS in the review of the appeal. Review Process: The ORSC Staff will forward the response submitted by the investigator to the subcommittee Chairperson. The ORSC Staff will place the appeal for discussion at the upcoming full committee meeting.

Investigators will be given the option of contacting the IRB Chairperson to discuss their appeal and any additional supporting information prior to submitting their written response to CPHS. Investigators will be given the opportunity to attend the next scheduled CPHS meeting to discuss their appeal and answer any questions posed by CPHS regarding the IRB submission and any supporting documentation.

The ORSC Staff will notify the investigator in writing of CPHS final decision regarding the current appeal. In this notification, investigators will be informed that they can direct additional unresolved questions, express concerns, and convey suggestions to the Executive Committee. The decision of CPHS to disapprove, suspend, terminate, or modify submitted materials can not be overruled by the Institutional Official. There are no limitations placed on the appeal process, allowing investigators to appeal decisions and resubmit information as frequently as warranted.

Responding to Subjects Questions and Concerns

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).