21 CRF 312.60
An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator’s care; and for the control of drugs under investigation. An investigator shall, in accordance with the provisions of part 50 of this chapter, obtain the informed consent of each human subject to whom the drug is administered, except as provided in 50.23 or 50.24 of this chapter
21 CRF 812.100
An investigator is responsible for ensuring that an investigation is conducted according to the signed agreement, the investigational plan and applicable FDA regulations, for protecting the rights, safety, and welfare of subjects under the investigator’s care, and for the control of devices under investigation. An investigator also is responsible for ensuring that informed consent is obtained in accordance with part 50 of this chapter. Additional responsibilities of investigators are described in subpart G.
Eligible to serve as the PI
NOT eligible to server as the PI
Compounds are extracted from natural substances or synthesized in the lab and analyzed for therapeutic value
Pharmacodynamics: the observed effect resulting from a certain drug concentration
Pharmacokinetics: Describes the drug concentration-time courses in body fluids resulting from administration of a certain drug dose
Toxicology: Tests the toxicological effects of an agent, including carcinogenicity
Animal Studies: Common animal models for studying compound safety and efficacy include mice, rats, pigs, dogs, and monkeys
Objectives should be clearly stated as a hypothesis to be tested
Sufficient background information should be included so that the rationale for the study is clear
Patient Eligibility Criteria
Inclusion and Exclusion criteria should be explicitly stated
Information should include product description, storage requirements, stability, route of administration, and toxicity information
Clinical Trial Blinding
Human behavior is influenced by what we know or believe. In research there is a particular risk of expectation influencing findings, most obviously when there is some subjectivity in assessment, leading to biased results. Blinding (sometimes called masking) is used to try to eliminate such bias.
Double blind: usually refers to keeping study participants, those involved with their management, and those collecting and analyzing clinical data unaware of the assigned treatment, so that they should not be influenced by that knowledge.
Double-Dummy: two active compounds, blinding is possible using this method. For example, if we want to compare two medicines, one presented as green tablets and one as pink capsules, we could also supply green placebo tablets and pink placebo capsules so that both groups of patients would take one green tablet and one pink capsule.
Single blind trials: (where either only the investigator or only the patient is blind to the allocation) are sometimes unavoidable.•Open (non-blind) trials. In trials of different styles of patient management, surgical procedures, or alternative therapies, full blinding is often impossible.
The FDA considers blinded clinical trials ethical if they meet the following criteria:
IND Submission Contents
When to Submit an IND
The FDA will notify the PI of approval via formal correspondence containing an IND number and a date of approval. All correspondence and original submission materials should be maintained in the regulatory binder.
Includes information and cautions derived from pre-clinical research
Serves as the official labeling for an investigational drug prior to FDA approval; subsequently, the approved package insert becomes the official labeling
If dangerous side effects are found, the drug is taken off the market or a Black Box may be added
Berlin Code of Ethics: World’s first official regulation of human experimentation, barring non-therapeutic interventions without voluntary consent, as well as experiments on minors and others judged vulnerable or incompetent.
The Nuremberg Code: International code of ethics established in response to inhumane Nazi human experimentation during WWII. The Nuremberg Code established four principles:
▫ Informed Consent
▫ Absence of Coercion
▫ Properly formulated scientific experimentation
▫ Beneficence towards experiment participants
Kefauver-Harris Drug Amendments: Passed to ensure drug efficacy and greater drug safety; drug manufacturers are required to prove to the FDA effectiveness of their products before marketing them and tests for safety during pregnancy are required before a drug can receive approval for sale in the U.S. As a result, the FDA is given closer control over investigational drug studies and FDA inspectors were granted access to additional company records.
Declaration of Helsinki: A statement of ethical principles stating that in medical research on human subjects, considerations related to the wellbeing of the human subject should take precedence over the interests of science and society. This document is widely considered the cornerstone of human research ethics.
The Belmont Report: The National Research Act led to the Belmont Report, which outlined 3 basic principles:
▫ Respect for persons
Respect for persons: Informed Consent
Beneficence: Benefits in research should outweigh the risks
Justice: Equality in selection and opportunity to participate in research
Code of Federal Regulations (CFR):
International Conference on Harmonization: Good Clinical Practice (ICH GCP E6)
Institutional (IRB) versus Central IRB (usually selected by sponsor but can be WIRB, Quorum or others)
The Institutional Review Board (IRB) was established in accordance with federal regulations governing the use of human subjects in research.
The IRB reviews and surveys research to ensure the protection of the rights and welfare of all research subjects.
Investigators cannot initiate or change research protocols until they have received IRB approval.
Required: CITI Web Based Training or other similar program
Required: GCP for Clinical Trials with Investigational Drugs and Medical Devices (U.S. FDA focus) is suitable for individuals proposing to conduct clinical trials of drugs and devices primarily in the U.S. and/or who would prefer a more U.S. FDA-centric curriculum.
Recommended: Clinical Research Coordinator (CRC)CITI Program’s CRC course provides a foundational training specifically focusing on operational and regulatory elements necessary for the ethical conduct of clinical research, while at the same time it is specifically tailored for the needs of clinical research professionals. It offers learners a foundation that expands beyond but is directly connected to theHuman Subjects Research (HSR) andGood Clinical Practice (GCP) ICH training.