Investigator Handbook
Chapter 1: Introduction to Human Subjects Research

The Principal Investigator of any research is the ultimate protector of the research participant’s rights and safety, and is obligated to be personally certain that each participant is adequately informed and freely consents to participate in the research.  The investigator must personally assure that every reasonable precaution is taken to reduce to a minimum any potential for harm to the participant.  The investigator also assumes responsibility for compliance with all Federal, State, and institutional rules and regulations related to research involving humans and human subject-derived information and materials.  Investigators may not initiate any research involving humans without prior review and approval by the Committee for the Protection of Human Subjects (CPHS), the IRB for UT Health Science Center at Houston.

Because all research involving human subjects must be reviewed by the CPHS, this handbook will provide each investigator with the information necessary to successfully submit for review the following types of CPHS submissions and review considerations:

Ethical Principles

It is important to esteem ethical principles in research with human subjects not only for the sake of the human subjects, but also for the institution.  As human subject protection is one of the highest priorities at UT Health Science Center, it is necessary to develop our practices, procedures, and regulations to reflect this respect for the ethical principles which have formed the following guidelines used today by IRBs.

The Nuremberg Code

After it was discovered that non-consenting war prisoners in concentration camps were the subject of coerced medical experiments by Nazi doctors during World War II, the Nuremberg Code was developed which required for any medical experimentation, voluntary informed consent by the human subject, the absence of coercion, properly formulated scientific experimentation, and beneficence towards the human participants.  The Nuremberg Code has since been incorporated into the laws of many states and countries.

The Declaration of Helsinki

The World Medical Association spent more than ten years working on the statement of ethical principles that became known as the Declaration of Helsinki.  This document defined rules for “therapeutic” and “non-therapeutic” research.  It repeated the Nuremberg Code requirement for consent for non-therapeutic research, but allowed enrolling certain patients in therapeutic research without consent.  The Declaration of Helsinki also allowed legal guardians to grant permission to enroll subjects in both therapeutic and non-therapeutic research, and recommended written consent - an issue not addressed in the Nuremberg Code. In addition, the Declaration of Helsinki requires review and prior approval of a protocol by an IRB.  Several revisions have been made to this document, including a Clarification, and it is still under revision today.  It has also become the backbone for the International Conference on Harmonization guidelines for Good Clinical Practice, found later in this chapter. 

The Belmont Report

After an unethical study on syphilis enrolling poor rural African-American men who were both misinformed as to the purposes of the study and were not treated for the disease, the federal government commissioned the “National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.“  As a result, “Ethical Principles and Guidelines for the Protection of Human Subjects of Research”, was written in 1979, providing the cornerstone for the ethical treatment of human subjects of research and also federal legislation.  This commission is the result of the National Research Act, passed by Congress in 1974; the document became known as the Belmont Report at the time of its publication. The three basic principles of the Belmont Report are respect for persons, beneficence, and justice.

Respect for persons is shown by the use of informed consent, and safeguards for vulnerable populations such as children, pregnant women, and prisoners. Other important concerns of respect for persons are privacy and confidentiality

Beneficence has two general characteristics: do no harm, and maximize benefit while minimizing risk. Maximizing benefit goes beyond the Hippocratic Oath of “do no harm” rather promoting “do good”.

Good Clinical Practice

The International Conference on Harmonization guidelines for Good Clinical Practice, ICH-GCP, is a set of international guidelines for conducting clinical trials adopted by the European Union in 1996, and by Japan and the United States in 1997. Good Clinical Practice (GCP) guidelines outline a standard for designing, conducting, recording and reporting trials that involve human subjects. Compliance with this standard provides public assurance of two goals:

• The rights, safety and well being of clinical research trial participants are protected.
• The clinical research data is credible and meets regulatory requirements of the European Union, Japan, and the United States.

The Thirteen Principles of Good Clinical Practice

1. All trials are conducted ethically, as defined by Declaration of Helsinki, rigorously, as defined by ICH, and in accordance with applicable regulations.
2. Benefits outweigh risks for each patient.
3. Rights, safety and well-being of patients prevail over science.
4. All available non-clinical and clinical information on any investigational agent can support the trial as designed.
5. All trials are scientifically sound and clearly described.
6. All clinical trials have current IRB approval.
7. Medical decisions and care are the responsibility of qualified health care professionals, specifically physicians, and, if applicable, dentists.
8. Everyone involved in the study is qualified by training, education, and experience.
9. Informed consent is given freely by every participant.
10. All study documentation is recorded, handled, and stored to allow accurate reporting, interpretation, and verification.
11. Confidentiality of subjects is respected and protected.
12. Investigational products maintain Good Manufacturing Practice in storage, manufacturing, and handling.
13. Systems to ensure quality are implemented in all aspects of the trial.

The Principal Investigator (PI) is ultimately responsible for ensuring the protection and safety of the research subjects and also ensuring integrity of the research; therefore, it is important that principal investigators and all study personnel know, understand and conduct clinical research studies according to these principles.

Scientific Pre-review

Scientific pre-review is conducted to ensure that all research involving human subjects is meritorious.  The pre-reviews are available for research protocols that have not previously undergone acceptable peer review but are not required for protocols qualifying for exempt review or being conducted under an IDE, IND, or HDE  (Human Research Protection Policy and Procedure (HRP PP) IV.03 Scientific Pre-Review). 

Scientific pre-reviews are initiated through the iRIS system and can be conducted during the preparation of the CPHS application.  This process typically takes about 2 weeks.
The pre-review is conducted by a committee that includes a member of the Office of Research executive staff, the applicant’s department head, and an expert designated by the Office of Research.  The expertise for the third member of the committee would be in either: study design and methodology, the therapeutic area, or some scientific aspect of the research.

The protocol is assessed using the following criteria:

• Is the rationale for the study design clearly stated and scientifically sound?
• Are the specific aims and objectives of the study clearly stated and measurable?
• Are the standards for conducting the research in line with guidelines developed by relevant professional associations and scholarly disciplines?
• Does the research rely on the least risky procedures that are clinically/scientifically sound and appropriate to the purpose of the research?
• Is the study design adequate to achieve the specific objectives of the research?
• Are statistical considerations, including sample size and justification, estimated accrual/duration, and statistical analysis clearly described and adequate to meet study objectives?
• Are the Principal and Co-Investigators well qualified to conduct the study?
• Is the proposed subject population appropriate?
• Are the data to be collected necessary to meet study objectives?
• Has an adequate literature review been conducted to support the study?

Upon completion of the review, the pre-review committee forwards the review to the applicant and the CPHS. The review certifies whether the research meets appropriate scientific standards, and may include comments and recommendations.  The investigator may still submit the CPHS protocol in the event of a negative decision; however, it is strongly advised that the appropriate revisions be made in order to receive a positive review by CPHS.