The Food and Drug Administration (FDA) recently released a Draft Guidance for Industry, in the form of Question and Answer (Qs & As) regarding “Expanded Access to Investigational Drugs for Treatment Use“—also commonly known as “compassionate use.”
The draft guidance is intended to provide information for industry, researchers, physicians, and patients about the implementation of FDA’s regulations on expanded access to investigational drugs for treatment use under an investigational new drug application (IND) (21 CFR part 312, subpart I), which went into effect on October 13, 2009.
Since 2009, FDA has received a number of questions concerning its implementation of these regulations. As a result, FDA is providing guidance in a question and answer (Q & A) format, addressing the most frequently asked questions.
In separate draft guidance, FDA is providing its thinking on questions concerning its regulations on charging for investigational drugs under an IND (21 CFR 312.8), which also went into effect on October 13, 2009. Information related to charging for investigational drugs made available under expanded access programs is in that draft guidance.
Comments on both draft guidance documents are due July 8, 2013.
Background on Expanded Use Regulations
These regulations contain the requirements for the use of investigational new drugs or approved drugs where availability is limited by a risk evaluation and mitigation strategy (REMS), when the primary purpose is to diagnose, monitor, or treat a patient’s disease or condition. Under these regulations, there are three categories of expanded access based on the size of the patient population to be treated:
- Individual patient access, including for emergency use;
- intermediate-size patient population access; and
- larger population access under a treatment protocol or treatment investigational new drug application (IND).
These regulations are intended to facilitate the availability of investigational new drugs, or approved drugs where availability is limited by a REMS, to patients with serious or immediately life-threatening diseases or conditions who lack other therapeutic options and may benefit from investigational therapies.
Expanded Access to IND’s
FDA first clarified that the terms expanded access, access, and treatment use are used interchangeably to refer to use of an investigational drug when the primary purpose is to diagnose, monitor, or treat a patient’s disease or condition. The distinction between expanded access and the use of an investigational drug in the usual studies covered under an IND is that expanded access uses are not primarily intended to obtain information about the safety or effectiveness of a drug. Expanded access, access, and treatment use may also refer to use of an approved drug, where availability is limited by a REMS, for diagnostic, monitoring, or treatment purposes, by patients who cannot obtain the drug through the REMS.
Next, FDA explained that an access protocol submission should be used only if the sponsor seeking access has an existing IND in effect — typically, such a sponsor is a commercial sponsor with an existing IND under which the sponsor is developing the drug for marketing. When there is an existing IND in effect, FDA generally encourages the submission of an access protocol, rather than a new access IND, because having all access and clinical trial use consolidated under a single IND may facilitate earlier detection of safety concerns associated with a drug, and the administrative process is less burdensome for sponsors and FDA.
Alternatively,
an access IND submission generally should be used when: (1) there is no existing IND in effect for the drug, or; (2) there is an existing IND in effect for the drug, but the sponsor of the existing IND declines to be the sponsor of the access use (e.g., for an individual patient use, the sponsor of the existing IND may prefer that a patient’s physician submit a separate individual patient IND).
For administrative purposes (e.g., tracking), FDA distinguishes between access INDs and access protocols, the different categories of access, as well as between emergency and non-emergency individual patient access. This results in the following 8 subcategories of access submissions:
(1) Individual patient IND (also referred to as a single patient IND)
(2) Individual patient protocol (also referred to as a single patient protocol)
(3) Emergency IND
(4) Emergency protocol
(5) Intermediate-size patient population IND
(6) Intermediate-size patient population protocol
(7) Treatment IND
(8) Treatment protocol
With respect to who can submit these types of requests, FDA provided the following clarifications. If there is an existing IND for the drug, either the sponsor of the existing IND or a licensed physician may make an individual patient expanded access submission (21 CFR 312.310(b)(1)). The sponsor of the existing IND (e.g., a pharmaceutical company) can submit an individual patient access protocol to its existing IND. In this scenario, the sponsor of the existing IND is also the sponsor of the access protocol, and the patient’s physician is the investigator for the access protocol.
Alternatively, the sponsor of the existing IND can instead submit an individual patient access IND and cross-reference information in its existing IND to support the individual patient access IND. In this scenario, the sponsor of the existing IND is also the sponsor of the access IND, and the patient’s physician is the investigator for the access IND.
In addition, a patient’s physician can submit an individual patient access IND for his/her patient. In this scenario, when the patient’s physician submits an access IND, the patient’s physician is both the sponsor and the investigator — in other words, he or she is considered a “sponsor-investigator.” The physician may satisfy some of the access submission requirements by referring to information in the existing IND if the physician obtains permission from the sponsor of the existing IND to do so (see Q5 above).
If the physician obtains this permission from the sponsor of the existing IND, the physician should provide FDA a letter of authorization from the sponsor of the existing IND that permits FDA to reference the sponsor’s IND. If the sponsor of the existing IND does not authorize reference to the IND, the physician sponsoring the access IND must include in the IND all of the information required to support the access IND.
A patient’s physician may not submit an individual patient access protocol to an existing IND for which the patient’s physician is not the sponsor (see 21 CFR 312.30).
When an access IND (not for emergency use) is submitted, the treatment use of the drug may begin when the IND goes into effect and IRB approval has been obtained consistent with 21 CFR part 56 (see 21 CFR 312.305(c)(4)). As is true for any new IND, an access IND goes into effect 30 days after FDA receives the IND or on earlier notification by FDA (21 CFR 312.40 and 312.305(d)(1)).
For a treatment protocol, however, access may not begin until 30 days after FDA receives the protocol or on earlier notification by FDA (21 CFR 312.305(d)(2)(ii)), and IRB approval has been obtained consistent with 21 CFR part 56 (see 21 CFR 312.305(c)(4)).
Because having all clinical trials and expanded access programs for a drug under a single IND may facilitate identification of safety concerns and ease the administrative burden for both sponsors and FDA, it is preferable for sponsors to submit an individual patient access protocol to an existing IND when possible. FDA reiterated that regardless of who the sponsor is, patients can only obtain access through a licensed physician.
The patient’s physician plays a crucial role in determining if access is appropriate. FDA may permit expanded access to a drug for an individual patient when the criteria in 21 CFR 312.305(a), applicable to all types of access, and the criteria in 21 CFR 312.310(a), specific to individual patient access, are met. For these criteria to be met, both the patient’s physician and FDA must make certain determinations.
The patient’s physician must determine that the probable risk to the patient from the investigational drug is not greater than the probable risk from the disease or condition (§ 312.310(a)(1)). The patient’s physician should make this determination based on the information about the drug available to the physician and the physician’s knowledge of the patient’s clinical situation.
As with all types of expanded access, FDA must determine, based on the information available to FDA, that the potential benefit justifies the potential risks of the treatment use with the drug and that those risks are not unreasonable in the context of the disease or condition to be treated.
In addition, to authorize the expanded access use, FDA must determine that the patient has a serious or life-threatening disease or condition and no other comparable or satisfactory therapeutic options ((§ 312.305(a)(1)), that providing access will not interfere with development of the drug for the expanded access use (§ 312.305(a)(3)), and that the patient cannot obtain the drug under another IND or protocol ((§ 312.310(a)(2))(e.g., in a clinical study of the drug).
In explaining how FDA determines when to deny a request, the agency noted that each individual patient request must be treated uniquely. For example, a patient may have a different stage of the disease or different tumor type than previous patients who were permitted access to the drug and, therefore, may have a different benefit/risk ratio.
Similarly, a patient may have a co-morbid condition not present in previous patients who obtained access that would make the risk unacceptable. FDA may also become aware of new safety signals or information about effectiveness that change the benefit/risk ratio such that the risk is no longer acceptable for the patient. In cases such as these, access to additional patients might be denied.
There also may be nonclinical reasons for denying access. For example, a patient seeking access may be able to enroll in a clinical trial that was not accessible to a previous patient who was granted access (e.g., because the previous patient met criteria for exclusion from the trial or the trial was geographically inaccessible to the previous patient). FDA could also have become aware, since authorizing previous requests for access, that access is impeding the clinical development of the drug and, on that ground, deny further requests for access.
With respect to chronic diseases, FDA explained that the agency may authorize multiple courses of therapy or chronic therapy for individual patient access, including authorizing individual patient access to treat a chronic disease or condition that requires extended treatment. F DA generally authorizes such individual patient access when the circumstances of the treatment are well-defined and reasonable in light of the available evidence to support use of the drug. To fairly weigh the risks and benefits of a drug for use for individual patient access, FDA believes the planned course of therapy should be well-defined because it will usually be necessary to consider the planned dose and duration of therapy in relation to what is known about the occurrence of toxicity for that dose and duration of therapy.
Therefore, FDA typically authorizes access for an extended duration for the treatment of a chronic condition when the patient’s condition and the information available about the safety of the drug support an extended duration of treatment, but does not typically authorize access of unspecified duration at the discretion of the treating physician.
Next, FDA explains that the agency may authorize expanded access for an individual patient without a written submission if there is “an emergency that requires the patient to be treated before a written submission can be made.” The licensed physician or sponsor, however, must agree to submit an expanded/ access IND or protocol within 15 working days of FDA’s authorization of the use (21 CFR 312.310(d)). FDA believes this regulation means that it is appropriate to request individual patient access using the emergency procedures described in 21 CFR 312.310(d) when treatment of the patient must occur within a very limited number of hours or days. FDA intends to scrutinize emergency requests and to authorize access for such requests only when the situation is a true emergency
For an emergency use, access to the drug may begin upon verbal authorization (usually over the telephone) by the reviewing FDA official. Because there typically will not be time to obtain prior IRB approval of the use, the emergency use must be reported to the responsible IRB within 5 working days of initiation of treatment.
FDA also clarified that it does not have the authority to compel a company to provide expanded access to its drug. When a company provides expanded access to its drug, it is doing so voluntarily.
Comments Regarding IRBs
Although FDA is inviting comment on the entire draft guidance (21 CFR 10.115(g)(1)(ii)(C)), FDA notes that it is particularly interested in receiving comments on question 10. Question 10 asks,
“Is Institutional Review Board (IRB) review and approval required for individual patient expanded access?”
In the draft guidance, FDA explains that under current regulations for all expanded access uses, including individual patient access uses, investigators are required to ensure that IRB review and approval is obtained consistent with 21 CFR part 56 (21 CFR 312.305(c)(4)). 21 CFR part 56 requires, among other things, that an IRB review the expanded access use at a convened meeting at which a majority of the IRB members are present (“full IRB review”) (21 CFR 56.108(c)).
However, FDA is aware of concerns that this requirement for full IRB review may deter individual patient access to investigational drugs for treatment use. FDA has encouraged use of central IRBs for review of expanded access uses to address these concerns. However, other options may be needed. Therefore, FDA is particularly interested in receiving comments on this issue, including
- to what extent the requirement for full IRB review of individual patient expanded access is a deterrent to patient access,
- whether FDA should consider alternatives to full IRB review of individual patient expanded access, and
- what alternative approaches may better facilitate access while providing appropriate ethical oversight.
Charging for Investigational Drugs Under an IND
In the second, but related draft guidance, FDA discussed the delicate issue of charging for investigational drugs. Providing background, FDA noted that for authorized charging for an investigational drug under a regulation that was published in 1987 many years, the agency.
In 2009, FDA revised its 1987 charging rule for three principal reasons: (1) to take into account circumstances concerning charging for investigational drugs in a clinical trial that were not anticipated when the rule was written; (2) to set forth criteria for charging for investigational drugs made available under all three categories of expanded access described in the expanded access regulations that were also revised in 2009, and; (3) to specify the types of costs that can be recovered when charging for an investigational drug under an IND.
FDA first noted that it does not have a specific timeframe for responding to a request to charge for an investigational drug, but intends to respond with 30 days of receipt when possible.
Next, FDA clarified that only the sponsor of the IND must request FDA’s authorization to charge for an investigational drug for use under the IND. For example, if the manufacturer of an unapproved drug is not the sponsor of the IND under which the drug will be used, the manufacturer is not required to obtain authorization from FDA to charge the sponsor of the IND for the unapproved drug. However, in such a situation, if the sponsor wants to charge patients to recover the cost charged by the manufacturer, the sponsor must obtain FDA’s authorization before it can begin charging patients.
FDA further clarified that it does not determine how the charging of the drug is carried out. FDA noted that it had no authority to require that the Centers for Medicare and Medicaid Services (CMS) reimburse for investigational drugs for which FDA has permitted charging and no authority to dictate reimbursement policy to private health insurance providers.
If a sponsor uses its own investigational drug in a clinical trial, the sponsor must satisfy the following requirements to charge for the drug:
- Provide evidence to FDA that the drug has a potential clinical benefit that, if demonstrated in clinical investigations, would provide a significant advantage over available therapies
- Demonstrate that the data to be obtained from the clinical trial are essential to establishing the drug is effective or safe for the purpose of obtaining initial approval, or would support a significant change in the labeling of an approved drug (e.g., a new indication, inclusion of comparative safety information)
- Demonstrate that the clinical trial could not be conducted without charging because the cost of the drug is extraordinary to the sponsor (21 CFR 312.8(b)(1)(iii)), and
- In its charging request submission, provide documentation to show that its calculation of the amount to be charged is consistent with the requirements of 21 CFR 312.8(d)(1). The documentation must be accompanied by a statement that an independent certified public accountant has reviewed and approved the calculation (21 CFR 312.8(d)(3)).
Sponsors must meet these requirements and obtain written authorization to charge from FDA before they begin to charge for an investigational drug. The agency also noted that a sponsor must obtain authorization to charge for a drug for trials involving unapproved uses of approved drugs.
FDA also clarified that the cost of a drug may be considered “extraordinary” to a sponsor because of manufacturing complexity, scarcity of a natural resource, the large quantity of drug needed because of the size or duration of the trial, or some other combination of these or other extraordinary circumstances. FDA noted that it will consider the financial reousrces available to a sponsor when determining if cost is extraordinary. Sponsors may continue to charge for investigational drugs through the entire length of the clinical trial, unless FDA speciies a shorter duration.
FDA also explained that a sponsor can only recover the direct costs of making a drug available to subjects in a clinical trial — that is, those costs that are specifically and exclusively attributable to providing the drug to clinical trial subjects. These include costs to manufacture the drug in the quantity needed to conduct the clinical trial for which charging has been authorized or costs to acquire the drug from another source, and costs to ship and handle (e.g., store) the drug.