V. PROTOCOLS USING INVESTIGATIONAL NEW DRUGS OR DEVICES

Use of Test Articles in the Clinical Center

"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:

• Approval status: The drug may be one not yet approved by the FDA and subject to an IND exemption, or one that is commercially available and FDA-approved for at least one indication. An approved drug could be proposed for a new use; combined in new ways with other approved drugs; combined in new proportions with other approved drugs; administered in alternate dosage forms or routes; or combined with new components, such as a coating or filler.
• Circumstances of administration: The drug may be administered to a participant in a controlled clinical trial or administered outside the original trial under expanded patient access to experimental drugs. There are four circumstances that arise when these features intersect:

Circumstance A: Use of an Investigational New Drug in a Clinical Research Study

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.

• Single-patient/single use (also referred to as compassionate use). This mechanism allows a patient to receive the IND even though the patient does not quite meet the specified protocol entry criteria, for example, being 63 instead of less than 60 years of age, or having a serum bilirubin of 1.2 when the entry criterion is less than 1.0. The drug companies that sponsor such protocols generally discourage this mechanism because deviating from careful selection rules can damage the study and reduce its value.

  This mechanism also can allow a patient to be given an IND to "treat" a serious illness when no satisfactory alternative therapy is available. IND's under trial at the CC or elsewhere may be used for the exemption. The physician ordering the drug must have the approval of the sponsor. The protocol consent document used in the ongoing trial can usually be used for these patients, but they must be informed that they are not protocol participants. FDA expects a full reporting of the outcome.

• Emergency-use IND (FDA rule). A test article may be used for a single patient in a life-threatening situation when no standard acceptable treatment is available and when the time for filing for an IND and obtaining IRB approval in the usual manner is insufficient. A temporary IND is granted by FDA, usually by telephone, with the understanding that the sponsor will submit a proper IND. Emergency use must be reported promptly to the IRB Chair. Further use of the test article in the institution is subject to IRB review.
• Treatment IND (FDA rule). This mechanism – added by FDA in 1987 and first used at the CC in December 1987 for ifosfamide and mesna in the treatment of refractory germ cell carcinoma – is intended to make an IND available to patients with a serious or immediately life-threatening disease. At the same time the sponsor can learn some information about efficacy and toxicity. Criteria for permitting the use of a treatment IND are as follows: the disease is serious or immediately life-threatening; no satisfactory alternative is available; and the drug is under study in a controlled clinical trial under an IND in effect for the trial; or all clinical trials have been completed and the sponsor of the clinical trial is actively pursuing marketing approval.

  The sponsor develops a treatment IND protocol and makes the drug available to licensed practitioners ("investigators"), who commit to the protocol-described handling of the test article for administration to patients. In the CC, the IRB approves the protocol and the protocol consent document, which must pass through the usual protocol track until a protocol number is assigned.

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.

Circumstance C: Use of an Approved Drug in a Clinical Research Study

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.

Circumstance D: Use of an Approved Drug in an Unapproved Manner in the Practice of Medicine

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.

Filing an "Investigational New Drug Application"

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:

• Selecting qualified investigators.
• Giving them information they need to conduct an investigation properly.
• Ensuring proper monitoring of the investigations.
• Ensuring that the investigations are conducted in accordance with the general investigational plan and protocol.
• Maintaining an IND that complies with all requirements with respect to the investigations.
• Ensuring that the FDA and all participating investigators are informed promptly of significant new adverse effects or risks of the drug.

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):

• Cover sheet: form FDA 1571, "Investigational New Drug Application (IND)," and form FDA 1572, "Statement of Investigator" (appendices D and E, respectively). The forms are available on the FDA website at http://forms.psc.dhhs.gov/, or from the CC Pharmacy Department and the PCSC.
• Table of contents
• Introductory statement and general investigational plan
• Investigator's brochure
• Protocol
• Chemistry, manufacturing, and control information
• Pharmacology and toxicology information
• Human experience with the investigational drug
• Additional information
• Relevant information

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:

• Phase I includes the initial introduction of an IND into humans. Phase I studies are typically closely monitored and may be conducted in patients or healthy clinical research volunteer subjects. These protocols are designed to determine the metabolism and pharmacologic actions of the drug in humans, to learn the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. During phase I, sufficient information about the drug's pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid phase II protocols. The total number of subjects and patients included in phase I protocols varies with the drug, but is generally in the range of 20 to 80.
• Phase II includes the controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks associated with the drug. Phase II protocols are typically well controlled, closely monitored, and conducted in a relatively small number of patients, usually no more than several hundred subjects.
• Phase III protocols are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting the effectiveness of the drug has been obtained. Phase III studies are intended to gather additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling. Phase III protocols usually include from several hundred to several thousand subjects.
• Phase IV protocols. Concurrent with marketing approval, the FDA may seek agreement from the sponsor to conduct certain post-marketing (phase IV) studies to delineate additional information about the drug's risks, benefits, and optional use. The protocols could include, but would not be limited to, studying different doses or schedules of administration than were used in phase II protocols, use of the drug in other patient populations or other stages of the disease, or use of the drug over a longer period of time.

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.

Reporting an Adverse Experience

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.

Annual Progress Reports to the FDA

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:

• Name of the Institute
• Protocol number assigned by the PCSC
• Name of the drug or drugs
• IND number assigned by FDA
• A brief narrative of the research results since the last report, including the numbers of patients (or healthy clinical research volunteers) who received the drug and the nature of any adverse experience. The sponsor should also provide the numbers of patients who completed or dropped out of the protocol and the reasons why.
• Any changes in the protocol or investigators
• A statement of whether the protocol has been discontinued and, if it has, the reasons for discontinuing.
• Signature of the PI
• Signature of the Institute Clinical Director
• Date of the report