For Companies
and Sponsors

With the changes brought about by the 21st Century Cures Act (Cures Act) and its reporting requirements, companies (i.e. developer, manufacturer, or distributor who sponsors an investigational product) have certain responsibilities around the transparency of how they manage expanded access (EA) requests. It is important that new and emerging biopharmaceutical companies bringing their first drug candidate(s) to market understand their responsibilities and know how to manage the EA process.

The term expanded access (sometimes referred to as “compassionate use” or “pre-approval access”) is used to describe treatment with an investigational product for a patient with a serious or immediately life-threatening illness when there are no comparable or satisfactory alternative treatments available and the patient is ineligible or unable to participate in a clinical trial. It is important to remember that these investigational drugs or biologics have not yet been approved by FDA and have not yet been proven safe and effective.

The Cures Act brought sweeping reforms intended to expedite the discovery, development, and delivery of new treatments and cures. As part of the new law signed December 13, 2016, companies with one or more investigational drugs in phase 2 or 3 clinical trials are now required to make public their policy for handling EA requests.

Companies may choose not to offer EA and include a statement to this effect in their EA policy; however, companies are still obligated to make that policy publicly available. See section 561 of the Food, Drug, and Cosmetics Act as amended. Companies receiving breakthrough, fast-track status or regenerative advanced therapy designations are required to make their EA policies public 15 days after the therapy receives its designation.

The policy may be generally applicable to all of a company’s investigational drugs, or it may be specific to each investigational drug by name. The policy must include:

• Contact information for the investigational product developer, manufacturer, or distributor to facilitate communication about expanded access requests
• Procedures for making an EA request to the company
• Anticipated time it will take the company to acknowledge receipt of a request
• General criteria used to evaluate and respond to a request
• A hyperlink or reference to the clinical trial record specific to the drug and submitted to ClinicalTrials.gov, if applicable.

This may be new territory for some companies that do not have prior experience or have products in the early stages of clinical development. It is important that all companies develop plans for how to address EA as they develop their new therapies.

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 institutional review board (which reviews the EA request and informed consent 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 expanded access 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 expanded access to an investigational product may be submitted as either an Investigational New Drug Application (IND) or as a new protocol to an already existing IND for the product.

When the physician submits a new IND for expanded access to an investigational 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 expanded access 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 expanded access 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 expanded access for multiple patients, companies may contact CDER’s Division of Drug Information at 301-796-3400 or druginfo@fda.hhs.gov.

In order to properly evaluate options and develop an appropriate EA Policy, a company has many things to consider.

RISK-BENEFIT ANALYSIS
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 investigational stages, production is limited to accommodate patients currently participating in clinical trials. Any commitment from a company to provide an investigational therapy to patients outside of trials requires having enough of the investigational 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 investigational therapy for EA must not interfere with the initiation, conduct, or completion of clinical trials that could support marketing approval or otherwise hinder the potential development of the drug and its release to the wider public.

COST
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 investigational 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 institutional review board (IRB) approval and FDA determines the treatment may proceed, a company will then arrange for distribution and transport of the therapy.

PATIENT CONSIDERATIONS
Each patient is unique. Patient information including age, gender, diagnosis, knowledge of any co-existing conditions, previous treatments, or previous participation in clinical trials 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.

BIOETHICAL CONSIDERATIONS
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 investigational drug?
• Are the potential risks of treatment with the investigational drug reasonable in the context of the patient’s disease or condition being treated?
• Is there another investigational 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?

TRANSPARENCY
Regardless of whether a company agrees to provide an investigational 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 informed consent is obtained in accordance with and to the extent specified by federal requirements. IRBs also ensure the patient has given his or her informed consent indicating, among other things, that the patient is informed that he/she will be treated with an investigational 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 informed consent 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.

REGULATORY IMPACT
Remember the FDA cannot require a manufacturer to provide its investigational therapy. Industry sometimes expresses concern about the impact patients treated with an investigational drug outside the clinical trial may have on the FDA’s assessment of the safety profile of their investigational drugs. However, a recent review of expanded access 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.

Companies are obligated to post their EA policy in a publicly-accessible location, such as their website, as specified by Section 3032 of the Cures Act. Posting an EA policy in the Expanded Access Navigator Company Directory can satisfy this requirement and provides a central location for physicians and patients to access information from multiple companies.

Although company policies differ, an expanded access policy typically incorporates the following elements.

• Purpose and philosophy behind the policy
  • This statement often references a commitment to bringing new, innovative therapies to patients by conducting rigorous clinical trials and obtaining marketing approval by the FDA and other regulatory authorities.
• Approach to requests for access to experimental therapies
  • Participation in clinical trials is the first and most preferable route.
  • If participation in clinical trials is not an option, physicians may consider other options, which may include expanded access programs managed by the company or single-patient expanded access.
  • Requests are considered on a case-by-case basis in a fair and equitable manner.
• General criteria used to evaluate such requests for individual patients
  • The patient has a serious or life-threatening condition with no satisfactory alternative.
  • Assessment that benefits outweigh the risks to the patient.
  • Assessment that the company has an adequate supply of the investigational medicine.
  • A determination that expanded access will not interfere with the company’s ability to complete clinical trials in a timely fashion or which might otherwise delay marketing approval and ultimately availability to all patients.
• Statement that a medically qualified physician should be the first point of contact with the company either by phone or email
  • The company may request additional information, including patient history, in order to fully evaluate the request.
  • If the physician will be the sponsor for the IND, he or she is required to obtain necessary ethical and regulatory clearances, including informed consent, as well as provide reporting on treatment outcomes.
• Commitment to acknowledging the request by a certain period of time, e.g., five working days
• Contact information 
  • ​​Such information may include a general email address, individual's name, web form, and/or telephone number. 

It is also helpful to indicate the name of the investigational therapies and the corresponding conditions for which each therapy may be made available.

See Sample Policies.

Once a company has developed its internal policy on expanded access and posted the policy in publicly-accessible locations such as its website and the Expanded Access Navigator Company Directory, patients and physicians researching potential options may approach the company with a request for EA to an investigational drug.

Below are some of the steps that the company may wish to take in handling these requests.

INITIAL INQUIRY
A physician approaches the company by phone, email, fax, or web form to make an inquiry about single-patient expanded access. If a patient makes the initial inquiry, the company should direct the patient to approach their physician to initiate this process.

EVALUATION OF REQUEST
A company representative, typically a clinical expert well-versed in the available treatment options, and the patient's physician discuss clinical options. The company gathers specific patient data and the current diagnosis to help determine if EA is the best option for the patient. At this point, the company representative may suggest other opportunities the physician should consider, such as participation in existing clinical trials, existing expanded access protocols, or available treatments by other manufacturers the physician may not have considered. In some circumstances, the physician may request expedited review in emergency situations.

LETTER OF AUTHORIZATION
If the company, in concert with the physician, believes that a single-patient IND should be pursued, the company will generally agree to issue the physician a Letter of Authorization (LOA) to reference the existing IND under which the investigational drug is being studied.

IRB REVIEW
As all expanded access, including single-patient EA, requires IRB review, the physician will need to gather and submit all of the necessary documentation for the IRB to review the treatment from the perspective of patient safety, including informed consent. Physicians seeking expanded access for a single patient may request the IRB chairperson or designated representative to sign off in lieu of full 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 physicians in finding an IRB and providing this Board with all of the necessary information 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.

EMERGENCY SITUATIONS
In the case of an emergency situation, FDA may provide authorization over the phone and treatment may be initiated without prospective IRB review, provided that the IRB determines there is insufficient time for full IRB review and approval. In these cases, the IRB is required to be notified within five (5) days of treatment.

FORM SUBMISSION
Once the LOA is received, the physician can submit the LOA to the FDA along with Form 3926.

FDA EVALUATION
An expanded access IND goes into effect 30 days after FDA receives the application unless FDA allows treatment to proceed before then or puts the IND on clinical hold (i.e., does not allow treatment to proceed). However, these INDs are often reviewed in much less than 30 days. Over the past 10 years, FDA has allowed 99% of all requests for expanded access to proceed, often with useful comments based on review of the IND. For example, sometimes a change in dosage to the treatment plan may be suggested. In cases of emergency situations, FDA’s review can be handled over the phone and authorization given in a few hours. After receipt of the single-patient IND, the relevant FDA staff reviews it. Among several considerations, FDA must determine that expanded access to the drug for the requested use will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval or otherwise compromise the potential development of the drug.

FOLLOWING FDA REVIEW 
Once the FDA allows EA to proceed, the company provides the investigational product to the requesting physician with all necessary information and guidance, which may include a contract between the company and the physician. The patient can obtain expanded access to the investigational drug only through treatment by a licensed physician. 

REPORTING REQUIREMENTS
There are reporting requirements on ClinicalTrials.gov regarding availability of EA that apply to the industry sponsor of an applicable clinical trial who is also the manufacturer of the drug. See additional guidance on registering EA records. As with any IND,  the sponsor, whether company or physician, is responsible for submitting to FDA an IND safety report and annual reports when the IND or protocol continues for one year or longer. For single-patient IND, regulations specify that after treatment the physician must provide to FDA a written summary of the results of the expanded access use, including adverse effects. While FDA considers adverse event information from expanded access in the safety assessment of a drug, it is very rare for this information to negatively impact regulatory decision-making.

EXPANDED ACCESS AND REAL-WORLD DATA COLLECTION
While not a requirement for regulatory submission, expanded access presents an opportunity to gather real-world data that can improve knowledge and help modernize drug development processes. Learn more in the Foundation's public meeting report on Leveraging Real-World Treatment Experience from Expanded Access Protocols.