Understanding Expanded Access
EA for individual patients depends on the cooperation and expertise of many. The physician (who applies on behalf of the patient and will oversee the treatment use), the drug company (that is developing the treatment), the (which reviews the EA request and document), and the FDA (which reviews the application to determine if the treatment may proceed) all have important roles and must collaborate for the EA process to work.
Below are questions each company should consider in determining access to its investigational drugs:
- How will offering EA impact your ability to conduct clinical trials?
- Do you have sufficient safety and efficacy data to determine risk-benefit?
- Does your organization have the time, personnel, sufficient investigational drug product and other resources to offer EA on a fair and equitable basis?
- Do you wish to offer single-patient EA or do you prefer an EA protocol (multiple patients)?
- Will you charge for EA?
- Does your investigational drug require special handling, transportation, or administration?
It is important to remember the FDA cannot require a manufacturer to provide its investigational therapy through an program.
Patients facing serious or life-threatening illnesses who have exhausted currently available treatment options and are ineligible or unable to participate in a clinical trial may decide to explore therapeutic use of investigational drugs with their healthcare providers. Both provider and patient work to research and identify investigational therapies which may help the patient. They may explore resources, including the Expanded Access Navigator, to learn more about companies, their policies and procedures, and the drugs that may be available through expanded access.
EXPANDED ACCESS IND VS EXPANDED ACCESS PROTOCOL
A request for to an product may be submitted as either an (IND) or as a new protocol to an already existing IND for the product.
When the physician submits a new IND for to an drug for treatment use by a single patient (i.e. single-patient expanded access IND), this new single-patient IND submission is separate and distinct from any existing INDs a company may sponsor and is intended only to make a drug available to a specific patient for treatment. A single-patient IND is typically used when there is no existing IND, or the industry sponsor of the existing IND declines to be the sponsor of the use and wishes the patient’s treating physician to take on the role of sponsor. In this instance, the industry sponsor of the existing IND may give permission to the treating physician, documented in the form of a Letter of Authorization (LOA), to reference content in the existing IND to satisfy certain requirements for an IND submission. The treating physician, in turn, will provide the executed LOA to FDA.
When an industry sponsor submits a new protocol for under an existing IND, the request may be for a single patient (i.e., single-patient expanded access protocol), or it may be for multiple patients (i.e., either intermediate-size protocol or treatment protocol). The FDA generally encourages industry sponsors to submit a new protocol to their existing IND rather than a new IND. For further information about for multiple patients, companies may contact CDER’s Division of Drug Information at 301-796-3400 or email@example.com.
In order to properly evaluate options and develop an appropriate EA Policy, a company has many things to consider.
The patient’s physician must determine that the probable risk to the patient from the investigational therapy is not greater than the probable risk from the patient’s disease or condition. It is important to remember that the company and/or FDA may have data that the physician and patient seeking EA may not be aware of that will inform their decision-making.
AVAILABILITY OF INVESTIGATIONAL PRODUCT
For many companies with therapies in stages, production is limited to accommodate patients currently participating in . Any commitment from a company to provide an therapy to patients outside of trials requires having enough of the product on hand for treatment. If supply is limited, the number of patients who can be accommodated through EA and how to apportion the available drug or biological will also be factors in the decision. Supply limitations are especially challenging for antibody, mRNA, cellular, and gene therapies.
IMPACT ON CLINICAL TRIALS
Providing the therapy for EA must not interfere with the initiation, conduct, or completion of that could support marketing approval or otherwise hinder the potential development of the drug and its release to the wider public.
Companies may only charge patients based on the company’s direct costs associated with making the drug available. The patient may have other associated medical costs, like travelling to see a specialist or for the facility to administer treatment. To learn more, see the FDA’s guidance on charging for drugs under an expanded access IND or protocol.
ADMINISTRATION OF THE THERAPY
Companies must be clear with the treating physician on the methods for administration of the therapy as well as any special handling or maintenance concerns about the proposed treatment. For example, if refrigeration is required, will the company ship it at the appropriate temperature, and are the physician and patient capable of seeing those requirements through to the actual administration at designated dosing?
If a request is granted, a company will generally provide an LOA to the physician. Once the physician secures (IRB) approval and FDA determines the treatment may proceed, a company will then arrange for distribution and transport of the therapy.
Each patient is unique. Patient information including age, gender, diagnosis, knowledge of any co-existing conditions, previous treatments, or previous participation in may all factor into a patient’s eligibility for EA.
Companies and providers must work together to fully assess what is known about the patient and the proposed therapy prior to proceeding with treatment to ensure that no undue harm comes to the patient.
Ensuring patient safety should be a top priority for biopharmaceutical companies and the FDA along with fairness and equality. Some companies are now beginning to consult bioethicists as they build out EA policies, and some have even included these experts in their review of individual EA requests. When formulating EA policies, biopharmaceutical companies should take into account a number of bioethical considerations:
- Are all patients treated fairly and equally?
- Do the potential benefits to a patient justify the potential risks of the treatment with the drug?
- Are the potential risks of treatment with the drug reasonable in the context of the patient’s disease or condition being treated?
- Is there another drug available with the company or at another company that is more suitable?
- How will patients be selected for treatment?
- How will patients be taken off treatment if the medication makes it to market?
- How will patients be taken off treatment if the medication does not make it to market?
Regardless of whether a company agrees to provide an therapy to treat a patient, companies are required to have EA policies in place. These policies should be easily accessible to both medical providers and patients, and should be as clear, concise, and transparent as possible.
INFORMED CONSENT AND IRB REVIEW
Informed consent is critical to: (1) disclosing to patients information they need to make an informed decision; (2) facilitating the understanding of what has been disclosed; and (3) promoting the voluntariness of the decision about whether or not to take the drug. Consent documents and related material must be reviewed by the Institutional Review Board (IRB) prior to treatment with the investigational drug, except for emergency expanded access use when there is not sufficient time to obtain prospective IRB review.
The primary purpose of IRB review is to ensure that the rights and welfare of human subjects are protected, including by determining that is obtained in accordance with and to the extent specified by federal requirements. IRBs also ensure the patient has given his or her indicating, among other things, that the patient is informed that he/she will be treated with an drug, there may be uncertainty about the safety and effectiveness of the product, and the benefits and risks have been adequately explained. In the case of non-emergency expanded access, treatment cannot be initiated until the IRB-approved form has been signed by the patient.
After reviewing the IRB documentation, the IRB can do one of three things:
- Option #1: Approve the proposed application
- Option #2: Require modifications to secure approval
- Option #3: Disapprove the application
The treating physician may seek a waiver of the requirement for full IRB review and instead seek concurrence by the IRB chairperson or another designated IRB member before treatment use begins. When single-patient IND is sponsored by a licensed physician, the physician is required to secure IRB review. Some physicians, especially those not affiliated with academic or large hospitals, may not have access to or be familiar with IRBs. In these cases, it may be helpful to assist the physician in finding an IRB to make their determination. There are independent IRBs that may be able to assist. A federal online database of available IRBs can be accessed here.
Remember the FDA cannot require a manufacturer to provide its therapy. Industry sometimes expresses concern about the impact patients treated with an drug outside the may have on the FDA’s assessment of the safety profile of their drugs. However, a recent review of requests that were received over a 10-year period demonstrated that only two of more than 10,000 drug development programs were put on clinical hold due to adverse events that occurred on EA use, and those two holds were eventually resolved, allowing the drug development process to continue.
See Question 26 in the Guidance for Industry for more information on why the FDA reviews adverse event data for expanded access INDs.