On June 2, 2016, FDA issued three final Guidances for Industry—two of the three are aimed at clarifying the expanded access applications and procedures, while the third discusses charging for investigational drugs under an Investigational New Drug (IND) application.
1. Expanded Access
The two expanded access Guidances for Industry, titled “Individual Patient Expanded Access Applications: Form FDA 3926” and “Expanded Access to Investigational Drugs for Treatment Use – Questions and Answers,” are part of FDA’s efforts to further accessibility to and streamline procedures for requesting individual access to investigational drugs. The Agency created Form FDA 3926 to aid physicians in submitting individual expanded access requests by withdrawing the requirement to complete and submit a full IND to seek use of an investigational drug. Form FDA 3926 may also be used for certain follow-up submissions, including the Initial Written IND Safety Report and Annual Report. However, only licensed physicians may use Form FDA 3926 – sponsors of existing INDs seeking to submit an individual patient expanded access protocol to its existing IND must submit an expanded access protocol (preferred by FDA) or a new expanded access IND and should include Form FDA 1571.
These new guidances include a number of provisions of note for the pharmaceutical and biotechnology industry, including FDA’s explicit recognition that the agency is unable to force drug companies to provide investigational products for expanded access treatment.
These two Guidances describe the procedures and timelines for processing of Form FDA 3926, the Form’s uses, and various details surrounding expanded access. FDA stated its intent to generally accept a completed Form FDA 3926 as compliant with regulatory IND submission requirements and as an appropriate request to waive the need for additional information normally required for INDs. The streamlined process is in accord with FDA’s recent history of granting the large majority of individual patient applications. The Guidances also state that in non-emergency situations, the investigational drug treatment may proceed after FDA notifies the physician or, if no notification occurs, 30 days after FDA receives the completed form.
Although the approval process has been made easier, patient safety and recordkeeping obligations remain intact. The physician behind the individual patient request IND is the sponsor-investigator and, therefore, is responsible for complying with the responsibilities for both study sponsors and investigators as applicable to expanded access use (described in subpart D of 21 CFR Part 312 and related guidance documents), including submitting IND safety reports and annual reports, and maintaining adequate drug disposition records. Informed consent requirements (21 CFR Part 50) and Institutional Review Board (IRB) approval requirements (21 CFR Part 56) must also be satisfied.
FDA has recognized that in full IRB review may be impractical in certain situations (e.g., in health care settings without established IRBs) and FDA will consider proposed options that might better facilitate individual patient expanded access while providing appropriate ethical oversight.
Emergency Expanded Access
One area that received significant attention in these Guidances is emergency use expanded access. FDA has clarified that if a patient needs emergency treatment before a written submission can be made to FDA, a request to use an investigational drug on an individual patient may be made by telephone or other rapid means of communication and an FDA official may give authorization for such use by telephone. The physician must first explain how expanded access use will meet general expanded access requirements and agree to submit an expanded access application within 15 working days of FDA’s initial authorization.
In addition, while IRB review and approval is generally required to treat a patient with an investigational drug, in emergency situations where there is not sufficient time for IRB pre-approval, use of the investigational drug on an individual patient may commence without such pre-approval (so long as FDA has given authorization for expanded access). The IRB must be notified of the emergency expanded access use within 5 working days of emergency use.
Other notable issues that FDA addressed in the new guidance documents include:
- FDA’s intention to generally not consider safety or efficacy information arising out of expanded access use in the context of new drug approvals
- Authorizing expanded access for more than a single course of treatment
- Considering multiple emergency use requests at the same institution without pre-approval by IRB
- Under what circumstances it is appropriate to request expanded access for multiple patients using an intermediate-size patient population expanded access IND rather than a treatment IND or protocol
- The possibility that FDA will ask a sponsor to transition an intermediate-size patient population expanded access IND or protocol to a treatment IND or protocol as enrollment increases
- Treatment using more than one investigational drug within a single expanded access IND or protocol
2. Charging for Investigational Drugs Under an IND
The other final Guidance for Industry issued on June 2, 2016 is titled “Charging for Investigational Drugs Under an IND – Questions and Answers.”
Following up on its 2013 draft guidance, FDA maintains its position that sponsors may charge, with FDA authorization, for direct costs incurred in making a drug available, from the onset of manufacturing to the point it arrives at its shipping destination (or for drugs acquired from another source as a finished product, acquisition, shipping, and handling costs). Examples of indirect costs – including IRB fees and expenses and costs associated with reporting to the IRB or FDA – are listed in the Guidance.
To be allowed to charge for an investigational drug for use under an IND clinical trial, the sponsor must provide and demonstrate a number of things to FDA, including providing cost recovery calculations accompanied by a statement that an independent certified public accountant has reviewed and approved the calculation, demonstrating an inability to conduct the clinical trial without charging due to extraordinary cost of the drug to the sponsor, and demonstrating the necessity of the clinical trial for initial approval or labeling change, among others. Extraordinary cost is described in 21 CFR 312.8(b)(1)(iii) and considerations include the financial resources available to the sponsor. Once FDA approves charging for an investigational drug, the sponsor may continue to charge for the drug for the course of the clinical trial unless otherwise specified by FDA.
A separate list of requirements governs charging for expanded access use, also included in this Guidance. Even if such a request is approved, the sponsor may only charge for an investigational drug for expanded access use for one year from the time of the FDA authorization unless FDA specifies a shorter period. Sponsors may apply for reauthorization, which FDA recommends be submitted at least 60 days prior to expiration of charging authority.
Notably, the agency also states that FDA authorization is not required for sponsors to recover subsequent costs incurred at a clinical trial site (e.g., pharmacy, nursing, equipment, and study-related procedure costs), as well as costs of drug delivery (formulation, packaging, instrumentation, monitoring, disposables, setup, etc.).
Form FDA 3926 can be found at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM504572.pdf
Form FDA 3926 instructions can be found at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM504574.pdf
Individual Patient Expanded Access Applications: Form FDA 3926 – Guidance for Industry:
Expanded Access to Investigational Drugs for Treatment Use – Questions and Answers – Guidance for Industry:
Charging for Investigational Drugs Under an IND – Questions and Answers – Guidance for Industry: