V. PROTOCOLS USING INVESTIGATIONAL NEW DRUGS OR DEVICES
"Test article" is the generic designation for any drug, biologic, or device that is subject to regulation under the Federal Food, Drug, and Cosmetic Act or the Public Health Service Act. At the CC, test articles are usually, but not always, experimental drugs. Test articles may not be introduced into interstate commerce until approved by the FDA for at least one indication, unless an exemption is granted by the FDA. (Contact the PCSC for a copy of title 21, Code of Federal Regulations, part 312 [21 CFR 312], for further details on this process.) The FDA grants exemptions for drugs when it receives an "Investigational New Drug Application" (IND) from a "sponsor." The acronym IND is also used to refer to an "investigational new drug," which is defined as a new drug or biological product that is to be used in a clinical investigation.
Each use of an IND has two distinctive features:
Sponsor, IND number, drug source, doses, monitoring, and outcome measurements are all described in the protocol. A protocol consent document describing the study's risks and benefits for potential research participants is also included with the protocol. The protocol goes through the usual primary and secondary reviews at the CC and is assigned a protocol number. The sponsor of protocols in this category must submit annual reports to FDA.
Circumstance B: Use of an Investigational New Drug for Individuals Who Do Not Meet Protocol Criteria
A variety of mechanisms are used for Circumstance B, with such labels as single-patient, emergency, and treatment exemptions. Fundamentally, exemptions are mechanisms for administering an IND to individuals ineligible for or not entered in the study of the drug.
Investigators may enter a patient in an exemption category if the sponsor agrees and the IRB Chair and Institute Clinical Director approve. The form NIH-2702, "Special Exemption from Research Protocol," should be completed and submitted to the IRB Chair and Institute Clinical Director. The form should describe the patient's situation, the type of exemption requested, the number of the protocol from which exemption is requested, the dosing plan, and details about the informed consent that will be obtained from the patient. Once the sponsoring Institute approves the request for exemption, the NIH-2702 form is sent to the CC Deputy Director for Clinical Care and Associate Director for Quality Assurance and Hospital Epidemiology for approval before the drug is administered. The approved NIH-2702 form is filed in the patient's medical record. All uses of exemptions should be listed in the sponsor's annual report to FDA.
The drug must be FDA-approved (for a particular indication), commercially available, and subject to a definite clinical research study of another condition – for example, the early trials of cyclophosphamide for rheumatoid arthritis after the drug had been approved and put on sale for the treatment of lymphomas. The protocol is prepared, reviewed, approved, and numbered in the usual manner. If the drug is to be used in a way or in circumstances that make it less safe than its approved use, or if the intent of the investigation is to support labeling or advertising changes, a sponsor is needed, and an IND must be in effect for study of the new use.
In Circumstance C, the test article is classified as an IND because, even though the drug is not new, the use is new. For the most part, this type of protocol is sponsored by a drug company interested in extending the range of indications for its product.
Physicians credentialed by the CC, like all licensed physicians, may use any approved drug for any indication that they believe would benefit the patient. The practitioner must be the final judge of how to prescribe an approved drug. Although FDA approval for a specific use may be lacking, information supporting that use may exist, even though the manufacturer's label does not indicate the specific use. This situation may occur when a pharmaceutical company has no economic incentive to gain FDA approval for an additional indication for an already approved drug. Circumstance D does not require the filing of an IND.
Using an approved drug in an off-label manner can make it harder to defend against a tort claim. Jurisdictions view the absence of labeling differently. Regardless of the jurisdiction, however, physicians should inform the patient of what is being done. Although the CC does not have official policies on the matter, the physician should consider placing a note in the patient's medical record describing the information exchanged with the patient.
The material presented in this section deals primarily with the responsibilities of an investigator with extra-NIH sponsorship. The responsibilities and issues applicable to the sponsor-investigator are addressed definitively in 21 CFR 312.
The regulations require that an "Investigational New Drug Application" (IND) be filed before starting any protocol that uses an unapproved test drug. The PI is responsible for recognizing when a proposed use of a drug requires filing of an IND with FDA. The IRB is responsible for ascertaining that an IND has been filed if needed. Investigators uncertain of the approval status of a drug should contact the Pharmaceutical Development Service (PDS) of the CC Pharmacy Department.
The FDA grants IND status for chemicals or biologic agents when such status is applied for by a "sponsor." The sponsor may be an individual, such as the PI or an AI, a pharmaceutical company, governmental agency, academic institution, or private organization. The sponsor could be the PDS of the CC Pharmacy Department, an Institute, or a Branch. For administrative reasons, only one entity should be designated as the sponsor. The sponsor is approved by FDA and is responsible for the following:
A sponsor who intends to conduct a clinical investigation that is subject to FDA approval should submit an "Investigational New Drug Application." The application should contain the following parts in the order presented (21 CFR 312.23):
After FDA receives the IND application, it will assign an IND number and forward the application to the appropriate reviewing division. The reviewing division will send a letter to the sponsor containing notification of the IND number assigned, date of receipt of the original application, address where future additions to the application should be sent, and the name and telephone number of the person at FDA to whom questions about the application should be directed. Protocols may not be initiated until 30 days after the day FDA receives the application. At the discretion of FDA, the initiation of the protocol may be delayed beyond the 30-day period.
A major sponsor of drug investigation at the CC is the Division of Cancer Treatment (DCT) of the NCI. The DCT has published guidelines on what the investigator should do to enable DCT to fulfill its responsibility. DCT's published rules distinguish between the FDA's different phases of drug studies, phases I through IV, and demand more strictness on agents in one phase than another:
An NIH individual, Institute, or program, such as the Clinical Therapeutic Evaluation Program, that is specifically designated by a sponsor to conduct a drug study is considered, in the CC, the "holder." Holders report progress, adverse effects, and proposed changes to the sponsor who, in turn, reports as required to the FDA. The sponsor and the holder can be the same entity or individual.
An adverse drug reaction or adverse experience is 1) an effect of a drug that is not intended or expected and that is severe enough to result in the discontinuation of the suspected medication or the administration of specific measures to overcome the adverse effect; or 2) a side effect of an experimental drug. The PI must report to the sponsor any effect, whether serious or unexpected, of a marketed drug, whether investigational or routine, approved or unapproved, or known to the reporter or not (i.e., blind placebo or agent).
Investigators who have received approval from FDA to initiate a human gene transfer protocol must report any serious event immediately to the local IRB, Institutional Biosafety Committee, OHRP (if applicable), the Office of Biotechnology Activities, and FDA. Written reports must also be filed with each group. The address of the Office of Biotechnology Activities is NIH/OBA, MSC 7010, 6000 Executive Blvd., Suite 302, Bethesda, MD 20892-7010. The telephone number is 301- 496-9838.
The sponsor of a drug must review promptly all information relevant to its safety obtained or received from any source, foreign or domestic. The information may be derived from clinical investigations, animal investigations, commercial marketing experience, reports in scientific literature, and unpublished scientific papers. The sponsor is responsible for reporting, in writing, to the IRB, the Institute Clinical Director, the CC Director (if the protocol is conducted in the CC), the FDA, as necessary, and all participating investigators any adverse experience associated with use of the drug that is both serious and unexpected. A serious adverse experience is one that suggests a significant hazard, contraindication, side effect, or precaution. An unexpected adverse experience is one that is not identified in nature, severity, or frequency in the current investigator brochure or in the risk information described in the general investigational plan. The notification to the FDA must be made within 10 working days after the sponsor's initial receipt of the information. Sponsors also must telephone FDA no later than three working days after receiving information about an unexpected fatal or life-threatening experience associated with use of an IND in protocols. For purposes of this statement, "life-threatening" means that the patient was, in the view of the investigator, at immediate risk of death from the reaction as it occurred; it does not include a reaction that, had it occurred in a more serious form, might have caused death. Fulfilling FDA requirements with respect to IND safety reports is the responsibility of the sponsor or the sponsor-investigator of the drug and not that of the holder. Sponsors should inform the holders about what they require of holders to fulfill their own sponsorship responsibilities to the FDA.
The IRB that approved the protocol should review all adverse experiences to determine if the PI should prepare an amendment to the protocol requesting continued accrual or approval of amended procedure(s), consent(s), or subject population. On the basis of the nature of the adverse experience, the IRB may terminate the protocol.
Sponsors are required to submit annual progress reports to the FDA. Investigators should submit a brief report of the progress of the investigation, which may include the annual report information required by 21 CFR 312.33, as part of the protocol's continuing review, submitting one document to the FDA and one to the IRB. Upon request, the CC Pharmacy Department will assist the sponsor with preparing the progress report. The sponsor, whether NIH or a pharmaceutical firm, should file directly with the FDA. The progress report required of NIH sponsors includes the following elements:
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