To provide guidelines for the use of investigational agents in patients who would otherwise not qualify for enrollment into a clinical trial or who, for some other reason, are unable to participate in existing trials.
Investigators occasionally see patients who might benefit from the use of an investigational agent, but who are unable or not qualified to participate in existing trials.
Compassionate Use: While not used in the U.S. Food and Drug Administration (FDA) or Department of Health and Human Services (HHS) regulations, the term compassionate use has been used to refer to the use of a test article for a patient who is desperately ill and unresponsive to other therapies or for whom no standard alternative therapies are available.
Early Access: A drug/device that is available to a patient prior to final FDA approval, but when it is almost approved.
Expanded Access: Providing an investigational drug/device to patients outside of the study protocol because it demonstrates a positive benefit for a particular indication.
Single Patient IND/Single Patient Use: Designed for one patient, and used when it has been determined that the patient does not qualify for any clinical trials which may otherwise be available (see Appendix A).
Regardless of the category of (compassionate) treatment use, all applications require:
- An investigator;
- Informed consent;
- A manufacturer who accepts responsibility for the use and communicates with the FDA;
- A drug/device supplier (who may also be the sponsor/manufacturer);
- Oversight by the IRB, which includes full board approval.
Compassionate Use Approvals – General Information
The terms “compassionate use” and “expanded access” do not appear anywhere in the regulations, but are general terms used to refer to treatments provided to seriously ill individuals who would benefit from an investigational agent, but who cannot enroll in an existing trial using the agent. Generally, the unusual step of authorizing use of an investigational drug or device for what is primarily a treatment purpose is warranted only for patients with serious diseases or conditions who are without satisfactory therapeutic alternatives. If the requirement for emergency use are not met, the patient may be enrolled under a compassionate use protocol, if allowed by the manufacturer.
As with a research protocol, compassionate use cases must be reviewed and approved by a majority of IRB members at a convened meeting before the subject is permitted to enter the study. Although these protocols often are not viewed as research, federal regulators still consider these patients to be research subjects and such distribution must be reviewed by local IRBs.
In some cases sponsors allow expanded treatment distribution of the study drug/device to needy patients who have exhausted other treatment options and cannot wait until the completion of a Phase III study and approval by the FDA. Such distribution is known as early access or expanded access.
The expanded access provisions in the FDA Modernization Act (FDAMA) makes clear that any individual patient, acting through a licensed physician, is empowered to seek to obtain an investigational agent for treatment use.
In addition to Full Board approval, compassionate use situations require approval from the Director of Pharmacy when the investigational agent will be a drug handled by a CHS pharmacy.
Types of Compassionate Use
Treatment use of experimental agents can generally be grouped into two broad categories according to the number of people treated: expanded access and single patient treatment.
- Expanded access – One Compassionate Use protocol is to be used for all patients with the same diagnosis. Much like a standard clinical trial, the IRB reviews the protocol and the informed consent documents, etc., after which eligible patients are enrolled in order to have access to the drug or device. Includes the National Cancer Institute’s Treatment Referral Center (TRC) protocols.
- Single Patient Treatment – FDA can grant a single patient use to receive a drug under an existing IND when a patient is ineligible for the specified protocol. Under a single patient IND, the existing commercial IND sponsor provides the agent and is responsible for reporting to the FDA. Single patient treatment requires FDA approval prior to each use.
Physician / Investigator Responsibilities
When requesting an investigational agent for compassionate use, the physician must consider the following questions:
- Is the patient ineligible or unable to participate in a research protocol? Have standard procedures or therapies been exhausted?
- Is there objective evidence that the investigational agent is appropriate for the disease for which the request is being made? (Published phase II data is usually required as objective evidence of activity).
- Is the drug/device likely to benefit the patient with acceptable risk?
A request for compassionate use may be considered if the answer to all the above questions is affirmative.
Prior to treating the patient, the Investigator must:
- First contact the manufacturer or a commercial sponsor that is willing to supply the drug for this use.
- Contact the CHS IRB to get a copy of the Compassionate Use Application (Appendix B) and an Office of Research number.
- Write a consent form. (If one is already available from the manufacturer or commercial sponsor, it may be used. In the case of expanded access trials, protocols and consent forms are already established).
- Submit the Compassionate Use Application. The CHS IRB requires full board review for each case.
- IRB approval must be obtained before treating the patient.
- Documentation of IRB approval, including the signed/dated consent form, must be retained in the patient’s medical record.
Each compassionate use mechanism differs in purpose and in the reporting and procedural responsibilities of the investigator (see Appendix A). It is therefore important that the investigator contact the sponsor/manufacturer immediately to determine how to proceed (i.e. who will provide the drug/device and how it will be distributed).
In order for the IRB to approve a request for compassionate use of an investigational agent, the CHS IRB will:
- Require the receipt of the FDA’s written approval for use (as received from the IND/IDE holder, either directly or via the physician/investigator).
- Issue an approval letter (contingent upon receipt of FDA’s written approval).
- A Request for Product Review Form will be completed and sent to the appropriate department along with the FDA approval letter.
- The cost of the device is to be limited to manufacturing, research, and development; IRB to receive amount confirmation from the IDE holder.
- After IRB approval is granted, the Cottage Health System Devices and HUDs table will be updated to include the newly approved compassionate use device and will be distributed to the appropriate individuals.
- If an investigational drug for compassionate use is to be provided within Cottage Health System, prior approval and coordination of the Pharmacy Department is required.
Addition of a Compassionate Use Arm to an Active Study
In some cases, it is acceptable for investigators to add a compassionate use arm to an IRB-approved active study. If the study is being conducted independently by an investigator, the investigator may, at the IRB’s discretion, add a compassionate use arm. If the investigator is participating in a multi-center trial, the investigator must check with the study sponsor (a compassionate use arm may already be established).
The compassionate use arm may be needed:
- for patients who do not meet the entry criteria;
- for patients who, for some other reason, cannot enroll in the regular part of the study;
- for patients who have completed study therapy but necessitate continuation of treatment;
- to allow access to the study drug after the study has closed to enrollment.
Instructions for adding a compassionate use arm to an active research study:
- Add an addendum to the study protocol explaining the need and reason for the compassionate use arm.
- A separate consent form must be used for study subjects enrolling in the compassionate use arm. The title should clearly identify it as compassionate use and the phrase “compassionate use only” should be added as a footer to the bottom of each page.
- No data can be collected from compassionate use patients as part of the regular study.
- The addition of the compassionate use arm must be submitted to the IRB as an amendment to the study.
In this situation, each additional patient enrolled does not require a separate full board review, but must be accounted for in writing at the time of continuing review of the active study.
(WORD document also available)
Detailed Guidelines and References
Group C / Treatment IND
Expanded access protocols outline a treatment regimen that will be used for a predefined patient group. Two specific types of expanded access programs are Treatment INDs and Group C.
In 1987, the agency promulgated regulations formalizing the Treatment IND mechanism that permits widespread access to an investigational drug:
- if there is no comparable or satisfactory alternative,
- if the sponsor is pursuing marketing approval with due diligence,
- if the drug is nearing the end of its development, and
- if the data support the conclusion that the drug may be effective for the intended use in the intended population.
A Group C / Treatment IND is a mechanism established by the FDA and the Division of Cancer Treatment and Diagnosis (DCTD) of the National Cancer Institute (NCI) to distribute investigational agents to oncologists for the treatment of cancer under protocols outside the controlled clinical trial.
Investigational agents for which the DCTD requests Group C / Treatment IND designation from the FDA are those which have demonstrated effectiveness in one or more specific tumor types. Such approval is not equivalent to formal FDA approval of effectiveness for this indication.
Group C treatment protocols are also open to registered investigators or any NCI-approved investigator. Group C / Treatment IND protocols come with a standard guideline for treatment, with a model informed consent document.
Single Patient IND / Single Patient Use
Single patient use generally refers to treatment use of an investigational drug for an individual patient that is not participating in a clinical trial. Single patient use may be requested by a commercial sponsor under an existing IND or by a physician-investigator under a new IND.
Clinicians seeking to use the investigational drug for a patient unable to participate in a clinical trial must submit a separate application for each patient to be treated.
Under this model, the investigator must obtain the drug from a willing manufacturer and must apply directly to the FDA for an IND. This application should include a completed 1571 form, an outline of the patient’s history, a treatment plan, and a commitment to obtain informed consent and IRB approval.
Single patient use approval may also be arranged either through the sponsor under a treatment protocol, or through the FDA by first obtaining the drug from the sponsor and then submitting a treatment IND to the FDA requesting authorization to use the investigational drug for treatment use.
It is up to the sponsor of the study to make the decision about whether to make investigational drugs open to non-research distribution – often it is a pharmaceutical company or the NIH or NCI. The sponsor must obtain permission from the FDA for treatment distribution, and the type of distribution depends upon the type of approval obtained.
NCI special exception protocols are open to any qualified investigator on a patient-by-patient basis, with the study protocol consisting of a 2 page form to be filled out by the investigator. The special exception mechanism is the functional equivalent of an emergency IND, but differs from it in that any registered investigator may obtain an agent directly from the DCTD, instead of having to obtain an IND from the FDA. The FDA provides retrospective approval after the protocol is cleared by NCI.
For NCI-sponsored protocols, the study drugs must be distributed to, and administered by, and investigator registered with the institute, with the exception of TRC protocols, in which clinicians at the pre-approved centers all have access to the drugs.
On completing therapy with the special exception agent, the investigator must also provide the NCI with a report of the treatment experience (called the Report of the Independent Investigator), which describes toxicity and efficacy.
If the commercial sponsor is unwilling to assume responsibility for a special exception, an investigator may perform the role of sponsor for a single patient treatment use.
The special exception mechanism is the functional equivalent of an emergency use IND application but differs from it in that any registered investigator may obtain an agent directly from the Division of Cancer Treatment and Diagnostics of the National Cancer Institute (DCTD), instead of having to obtain an IND from the FDA. The DCTD allows early access to investigational anticancer agents for patients who are unable to participate in clinical trials.
A special exception request may be considered for any investigational agent for which DCTD sponsors an IND. The DCTD currently sponsors over 200 INDs with the FDA for approximately 150 different investigational anticancer agents. Approval depends on meeting the standard criteria for non-research release of investigational agents and agent availability. Each special exception request is reviewed and approved on a patient-by-patient basis.
The DCTD makes investigational treatments available via a Treatment Referral Center (TRC) protocol for certain promising agents or high priority diseases. For TRC protocols, the study drug is provided to designated treatment referral centers, along with a standard protocol and informed consent. The IRB at each center must approve the protocol prior to enrolling patients. However, even if an expanded-access TRC protocol is in place for a particular investigational drug, a single treatment exception may be necessary for some patients.
The DCTD may make investigational treatments available via a TRC protocol for certain high promising agents or high priority diseases. TRC protocols can also be used as a mechanism to ensure equitable distribution of agents with limited availability. TRC protocols are initially offered to the NCI-designated Clinical and Comprehensive Cancer Centers. All patients enrolled on a TRC protocol must receive their investigational therapy at an NCI-designated Cancer Center.
Health care professionals may contact the Treatment Referral Center (TRC) regarding potential therapeutic options, either clinical trials or non-research programs, by telephone (301)496-5725 or FAX (301) 401-4870.
Briefing Document for the ODAC Single Patient Use of Investigational Anticancer Agents.
National Cancer Institute’s Treatment Referral Center and Non-Research (Compassionate) Use of Investigational Anticancer Agents. Am. J. Health-Syst. Pharm. 55: 651 – 660, 1998.
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