Marshall University
SUBJECT: Investigational Drugs, Devices, and Biologics
PURPOSE: To assure that investigators conduct research utilizing drugs, biologics, devices, diagnostics, and dietary supplements and food additives in compliance with the guidelines set forth by the Food and Drug Administration and other federal regulations as applicable.
POLICY: This policy covers the research under the auspices of this IRB and covered by FDA regulations. The FDA regulates clinical investigations (research) conducted on drugs, biologics, devices, diagnostics, and, in some cases, dietary supplements and food additives, also known as “FDA regulated test articles.” All such investigations are to be conducted in accordance with FDA requirements for informed consent and IRB review, regardless of funding source or sponsor.
SCOPE: This policy covers all research conducted within the purview of this IRB involving drugs, biologics, devices, diagnostics, and dietary supplements and food additives.
RESPONSIBILITY:
IRB Chairman – The Chairman is responsible for protecting the health, safety, and welfare of human subjects participating in research studies involving test articles.
IRB Members – The members are responsible for reviewing and monitoring research activities involving test articles to ensure safety for the human subjects and compliance with FDA and other federal regulations.
Principal Investigator - The investigator is responsible for the conduct of the study and for leading the team of individuals coordinating the study. These responsibilities include obtaining IRB approval, obtaining informed consent from each subject, following the investigational plan, complying fully with the regulations, protecting the rights, welfare and safety of the subjects, supervising the use and disposition of the test article, maintaining accurate, current, and complete records; and disclosing relevant financial information. FDA and DHHS regulations require the IRB to have policies and procedures to ensure prompt reporting to the IRB, FDA, OHRP of any unanticipated problems involving risks to human subjects and others. If the investigator provides an IND or IDE number then supporting documentation is required that verifies the number, such as a protocol from a sponsor, a letter from the sponsor, or letter from the FDA.
For VAMC Research: The PI is responsible for informing Pharmacy Service that IRB and R&D Committee approval has been obtained. This must be through the use of VA Form 10-1223, Report of Subcommittee on Human Studies, to be sent to Pharmacy Service. VA Form 10-9012, Investigational Drug Information Record, or superseding forms must be provided to the pharmacy by the PI as required in VHA Manual M-2, Part VII, Chapter 6, or superseding policy document. In addition a signed copy of VA Form 10-1086, must be sent to Pharmacy Service to document each subject’s consent to participate in the study. The PI must inform the Chief, Pharmacy Service, and the R&D Committee when a study involving investigational drugs has been terminated.
Sponsor - The
sponsor is responsible for
initiating the clinical investigation, and holding the
1. Drugs or devices:
1.1. 21 CFR §11 (Electronic records and electronic signature)
1.2. 21 CFR §54 (Financial Disclosure by Clinical Investigators)
2. Drugs and Biologics:
2.1. 21 CFR §210 (Current Good Manufacturing Practice In Manufacturing, Processing, Packing, Or Holding of Drugs; General)
2.2. 21 CFR §211 (Current Good Manufacturing Practice for Finished Pharmaceuticals)
2.3. 21 CFR §312 (Investigational New Drug Application)
2.4. 21 CFR §314 (Drugs for Human Use)
2.5. 21 CFR §320 (Bioavailability and Bioequivalence Requirements)
2.6. 21 CFR §330 (Over-The-Counter (OTC) Human Drugs Which are Generally Recognized as Safe and Effective and Not Misbranded)
2.7. 21 CFR §601 (Biologics Licensing)
3. Devices:
3.1. 21 CFR §812 (Establishment Registration and Device Listing for Manufacturers and Initial Importers Of Devices)
3.2. 21 CFR §812 (Investigational Device Exemptions)
3.3. 21 CFR §814 (Premarket Approval of Medical Devices)
3.4. 21 CFR §820 (Quality System Regulation)
3.5. 21 CFR §860 (Medical Device Classification Procedures)
IRB Coordinator - The IRB coordinator is responsible for maintaining documentation of emergency use of a test article and reporting the information at the next IRB meeting. The IRB coordinator will verify the IND or IDE number against the supporting documentation provided by the investigator. The IRB coordinator will also ensure that the protocols involving drugs include information allowing the IRB to determine whether FDA required and IND or IDE.
JURISDICTION:
When FDA regulated research is being
done at
The FDA regulations have important differences from the Common Rule requirements. These differences are:
(1) FDA regulations contain no Assurance requirement.
(2) Conditions for exemption, exception, and waiver of IRB review and informed consent requirements differ.
(3) FDA regulations require specific determinations for the IRB review of device studies.
(4) FDA regulations include specific requirements for reporting adverse events that are not found in the Common Rule, or DHHS regulations.
(5) DHHS regulations include specific additional protections for pregnant women, fetuses, and human in vitro fertilization; prisoners; and children
that are not contained in the Common Rule requirements. In April 2001, FDA issued regulations to protect children in research (20 CFR 50
Subpart D).
DEFINITION:
“Compassionate use” is the
provision of investigational drugs outside of an ongoing clinical trial to a
limited number of subjects who are desperately ill and for whom no standard
alternative therapies are available.
Test articles means any drug for human use, biological product for human use, medical device for human use, human food additive, color additive, electronic product or any other article subject to regulation under the act or under sections 351 or 354-360F of the Public Health Service Act.
Investigational new drug
(
Investigational device exemption (IDE) - An approved IDE permits a device not approved by FDA to be shipped to conduct clinical investigations of that device. Not all investigational devices need an IDE.
Medical Devices. FDA device regulations differentiate between significant risk (SR) and non-significant risk (NSR) devices. A significant risk device must have an IDE issued by the FDA, while a non-significant risk device determination by an IRB grants the device an IDE. Thus, if a clinical investigation is submitted to the IRB for a device that has an IDE, the device is considered a SR device. A SR device (a) is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject, or (b) is used in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject, or (c) is of substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject or (d) otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.
Adverse Event (AE) - is any reaction or undesirable event that occurs in conjunction with the use of a drug, biologic product, diagnostic agent, medical device, experimental procedure, or even accepted medical treatment or procedure (if part of a research protocol), whether or not the event is considered related to the drug treatment or procedures. Such events may be psychological, emotional, social, or physical and include any illness, sign, symptom, or clinically significant laboratory test abnormality that has appeared or worsened during the course of the experimental study regardless of causal relationship to the drugs and procedures under study. For observational studies (e.g., chart reviews, data base studies, surveys), deaths, life-threatening events or hospitalizations need not be reported as AEs. Any AE directly or indirectly related to the study, such as loss of confidentiality or emotional trauma are still reportable. In addition, reports of subjects having complaints about the experimental procedures or about the conduct of the investigators may be reported as AEs.
“Serious adverse drug experience” is defined as “any adverse drug experience occurring at any dose that results in any of the following outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect”.
Emergency use of a test article is defined as use of a test
article on a human subject in a life threatening situation in which no standard
acceptable treatment is available, and in which there is not sufficient time to
obtain IRB approval.
PROCEDURE:
If the investigator indicates that drugs are being used in the research and there is no IND, the IRB will use the worksheet “Criteria for Exemption from the Requirement for an IND.”
If the investigator indicates that devices are being used in the research to test their safety or efficacy and there is no FDA-issued IDE, the IRB uses the worksheet “Criteria for Exemption from the Requirement for an FDA-Issued IDE” to ensure that an FDA-issued IDE is not required.
For an abbreviated IDE, the IRB must determine whether a device involves significant risk (SR) or non-significant risk (NSR) to subjects. The determination of the risk level is based on the proposed use of the device and not just the device itself. Clinical research involving an investigational device classified by the sponsor as NSR may be submitted to an IRB for review without an IDE. The sponsor/investigator must provide the IRB with a risk assessment and the rationale used in making its NSR risk determination. The IRB will review the information and make its own independent determination that the device is SR or NSR.
(1) If the IRB disagrees with the sponsor’s NSR determination, the IRB will notify both the investigator and the sponsor of its determination. The sponsor will need to submit an IDE application to the FDA. The study will not begin until the FDA approves the IDE and the IRB approves the study.
(2) If the
IRB determines that the device is classified as NSR, the clinical investigation
may begin once IRB approval is obtained.
(3) If FDA agrees that a new device is substantially equivalent
to a device already on the market, it can be marketed without clinical testing.
However, if clinical data are necessary to demonstrate equivalence, any clinical
studies must be conducted in compliance with the requirements of the IDE
regulations, IRB review, and informed consent.
The sponsor is required to obtain
an IDE before the IRB will review a research protocol involving a significant
risk device. Protocols involving
significant risk devices do not quality for an expedited
review.
Radiology Devices and
Radioactive Materials. FDA is
responsible for regulating radiology devices and radioactive materials used in
healthcare and research. Oversight
at
Adverse Event (AE) Notification - INDs
Refer to the "Ensuring Prompt Reporting of Unanticipated Problems Involving Risks to Participants or Others" SOP for guidance on this issue.
Adverse Event Notification – IDEs
Refer to the "Ensuring Prompt Reporting of Unanticipated Problems Involving Risks to Participants or Others" SOP for guidance on this issue.
Relationship of IRB to IND/IDE Sponsors.
Unless specifically required by an
“Off-label” (Unapproved) Use of FDA-Regulated Products in Medical Practice. FDA regulations allow that physicians may use approved drugs, devices, and biologics in the course of the practice of medicine in any manner they see fit.
“Off-label” (Unapproved) Use of FDA Regulated Products in Research. Such activities require IRB review and approval.
Expanded Access to Investigational Drugs. Investigational products are sometimes used for treatment of serious or life-threatening conditions either for a single subject or for a group of subjects. The procedures that have evolved for an investigational new drug (IND) used for these purposes reflect the recognition by the FDA that, when no satisfactory alternative treatment exists, subjects are generally willing to accept greater risks from test articles that may treat life-threatening and debilitating illnesses. The following mechanisms expand access to promising therapeutic agents without compromising the protection afforded to human subjects or the thoroughness and scientific integrity of product development and marketing approval.
(1) Open Label Protocol or Open Protocol IND. These are usually uncontrolled studies, carried out to obtain additional safety data. They are typically used when the controlled trial has ended and treatment is continued so that the subjects and the controls may continue to receive the benefits of the investigational drug until marketing approval is obtained. These studies require prospective IRB review and informed consent.
(2) Treatment IND. The treatment IND is a mechanism for providing eligible subjects with investigational drugs for the treatment of serious and life-threatening illnesses for which there are no satisfactory alternative treatments. A treatment IND may be granted after sufficient data has been collected to show that the drug "may be effective" and does not have unreasonable risks. Because data related to safety and side effects are collected, treatment INDs also serve to expand the body of knowledge about the drug. Four requirements must be satisfied before a treatment IND can be issued:
(a) The drug must be intended to treat a serious or immediately life-threatening disease;
(b) There must be no satisfactory alternative treatment available;
(c) The drug must already be under investigation or the drug trials must have been completed; and
(d) The trial sponsor must be actively pursuing marketing approval.
Treatment IND studies require prospective IRB review and informed consent.
(3) Parallel Track Studies. FDA permits wider access to promising new drugs for HIV/AIDS related diseases under a “separate access” protocol that “parallels” the controlled clinical trials that are essential to establish the safety and effectiveness of new drugs. These “parallel track” studies require prospective IRB review and informed consent.
Expanded Access to
Investigational Devices. An unapproved medical device may
normally only be used in human subjects when the device is under clinical
investigation and when used by investigators participating in the clinical
trial. However, a health care
provider may wish to use an unapproved device to save the life of a subject, to
prevent irreversible morbidity, or to help a subject suffering from a serious
disease or condition for which there exists no alternative therapy. Four main mechanisms are utilized to
make unapproved devices available to subjects/physicians faced with these
circumstances. The sponsor must
agree and FDA must approve the use.
Under most circumstances such studies require
IRB review and informed consent.
(1) Single Subject/Small Group Access to Investigational Devices. Allows access to a device where the subject is not eligible for an ongoing clinical trial. The subject must have a serious condition/disease, with no alternative intervention available. Under some conditions, FDA may grant permission even if there is no p-existing IDE.
(2) Treatment Use/IDE. Allows wider access to a device during the clinical trial or prior to final action on marketing application. The subject must have a serious condition/disease, with no alternative intervention available.
(3) Continued Access to Investigational Devices. Allows access to a device while a marketing application is being prepared and reviewed, and can be used to collect additional evidence of safety and effectiveness, as well as to address new questions regarding the investigational device, such as labeling claims. There must be a public health need for the device, as well as preliminary evidence that the device is effective.
(4) Access under a formal protocol. Access in a controlled rate of enrollment and with no significant safety concerns identified for the proposed indication.
Gene Transfer
Research.
Gene transfer involves the administration of genetic material to alter the biological properties of living cells for therapeutic use. Gene transfer activities in humans are investigational and are regulated by the both the FDA and the National Institutes of Health (NIH) Office of Biotechnology Activities (OBA).
(1) FDA regulations require the submission of an IND for human gene transfer research through the FDA Center for Biologics.
(2) Department of Health and Human Services (DHHS) regulations specify that no individual may be enrolled in human gene transfer research until review has been completed by the NIH Recombinant DNA Advisory Committee (RAC), local Institutional Biosafety Committee (IBC) approval has been obtained, local IRB approval has been obtained, and the investigator has obtained all other regulatory authorizations from the subject (FR 196, October 10, 2000).
(3) While the RAC is advisory to the Director of the NIH, compliance with its guidelines is mandatory for all investigators at institutions that receive NIH funds for research involving recombinant DNA.
Emergency Use of a Test Article Without IRB Review.
An exemption permits the emergency use of an investigational drug, device, or biologic on a one-time basis per institution without IRB review and approval. The following conditions must be met for this type of emergency use:
(1) A human subject is in a life-threatening situation.
(2) No alternate standard acceptable treatment is available.
(3) There is insufficient time to obtain IRB approval.
(4) The emergency use must be reported to the IRB within five working days. This reporting must not be construed as an approval for the emergency use by the IRB.
(5) The investigator must obtain the informed consent of the subject for such an emergency use, except as described below.
The IRB#1 Chair verifies that conditions for the use meet the FDA regulatory requirements by evaluating the five-day report. If the IRB is notified of the use in advance, the IRB#1 Chair will also conduct a prospective evaluation of an investigator's intent to use a test article on an emergency basis in a life-threatening situation without prior IRB review to ensure that the conditions of the use will meet FDA regulatory requirements. Emergency use of a test article in a life threatening situation without prior IRB approval is research involving a human subject. However, the exemption does not apply if the use meets the DHHS definition of research involving human subjects. Such use may not be claimed as research as defined by DHHS regulations, nor may the outcome of such care be included in any prospective report of a research activity as defined in DHHS regulations.
Sample Letter Template for Emergency Use Reporting
Emergency Use of a Test Article Without Informed Consent. Regulations permit the emergency use of an investigational drug, device, or biologic without informed consent where the investigator and an independent physician who is not otherwise participating in the clinical investigation certify in writing all four of the following specific conditions:
(1) The subject is confronted by a life-threatening situation necessitating the use of the test article;
(2) Informed consent cannot be obtained because of an inability to communicate with, or obtain legally effective consent from the subject;
(3) Time is not sufficient to obtain consent from the subject’s legally authorized representative;
(4) No alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the subject’s life.
If time is not sufficient to obtain the independent physician determination before use of the test article, the actions of the investigator must be reviewed and evaluated in writing by an independent physician within 5 working days. The emergency use must be reported to the IRB within 5 working days. This reporting must not be construed as an approval for the emergency use by the IRB. (Note: This use without prospective IRB approval is research involving a human subject. However, the exception for the requirement to obtain informed consent does not apply if the use meets the DHHS definition of research involving human subjects.)
The Director, ORI verifies that conditions for the emergency use have been met by evaluating the five-day report.
“Compassionate” or “Humanitarian” Use of a Test Article. “Compassionate use” and “humanitarian use” are often meant to refer to the emergency use situations above discussed.
The sponsor in a marketing application of any drug, device, or biologic must submit certain information on financial interests and arrangements of clinical investigators conducting studies to FDA. The following financial arrangements must be disclosed to the sponsor:
(1) Any relationship between the study outcome and the value of the compensation made to the investigator.
(2) The investigator’s proprietary interest in the studied product, including but not limited to a patent, trademark, copyright or licensing agreement.
(3) Any equity interest in the study sponsor, ownership interest, stock options, or other financial interest.
(4) Any equity interest in a publicly held company that exceeds $50,000 in value.
(5) Significant payment of another type, which has a cumulative monetary value of $25,000 or more, made by the sponsors to the investigator(s).
(See the policy on Conflict of Interest of Investigators for the financial interests that investigators must disclose to the IRB.)
FOLLOW-UP RESPONSIBILITY: Director, Office of Research Integrity
REFERENCES: 20 CFR 50; 21 CFR 56; 21 CFR
312; 21 CFR 361; 21 CFR 812
FDA Modernization Act of 1997