Review of 3 Alternative Pathways to Access Non–FDA-Approved Drugs

Précis

Non–FDA-approved medications may be accessed for patient care via 3 alternative pathways: expanded access, the Right to Try Act, and off-label use, which are reviewed in this article.

Abstract

Navigating access to investigational or off-label medications for patients who have exhausted all other treatment options can be a challenge for institutions, physicians, and other health care providers. In this review, 3 alternate pathways are presented, compared, and contrasted: expanded access (EA; also referred to as compassionate use), access via the Right to Try Act (RTT), and off-label use. EA is regulated by the FDA and requires institutional review board oversight, approval by the medication sponsor or manufacturer, and informed consent from the patient. RTT allows patients, health care providers, and sponsors or manufacturers to bypass both regulatory and safety oversight. Off-label prescribing of FDA-approved medications remains a gray area where local guidelines and policies may help guide use of this access pathway. Understanding what alternative pathways are available for accessing medications outside FDA approval as well as the steps required and the limitations associated with each pathway is critically important for institutions and health care providers to best support patients.

Introduction

Although FDA-approved medications serve as the traditional treatment pathway for most patients in the United States, many are not candidates to receive these medications. Patients may need to seek treatment beyond medications granted FDA approval for various reasons, such as disease progression, treatment failure, rare tumors or diseases, and insurance coverage. These populations often include individuals with cancer or rare diseases and pediatric patients. Patients and health care providers may turn to clinical trials as the next treatment pathway in these cases, but not all patients will qualify for or have access to a clinical trial. In these situations, health care providers and patients may opt to leverage alternative pathways, such as expanded access (EA), access via the Right to Try Act (RTT), and off-label use of medications. However, navigating access to investigational or off-label medications for patients who have exhausted all other treatment options can be a challenge for institutions, physicians, and other health care providers. This article seeks to provide the historical context for why these alternate pathways are necessary and the legislation that made them possible as well as the requirements to access medication via these pathways.

In 1962, the Kefauver-Harris Drug Amendments to the Federal Food, Drug, and Cosmetic Act were signed into law, with a goal of ensuring both the efficacy and safety of medications marketed under FDA labeling.1 For the first time, drug manufacturers were required to prove to the FDA that their products were effective before marketing them.1 Today, the majority of medications, including biologics, used in the United States are obtained after FDA approval. Approval signifies that the agency has determined, based on the available evidence, that the medication is effective for use and that the benefit outweighs the risks when the medication is used according to the approved labeling. Passage of the Kefauver-Harris Drug Amendments provided an additional layer of efficacy and safety review. However, there are patients who have exhausted all available FDA-approved treatment options, are not candidates for clinical trials, and are unable to wait for new treatments to be reviewed and approved by the FDA. These patients may access medication through alternative pathways, such as EA, RTT, and off-label use.

Discussion

Expanded access

In 1987, revisions to investigational medication regulations broadened access to experimental drugs for patients with serious or life-threatening diseases for which there are no available alternative therapies.¹ This expanded access (EA) revision allowed patients with no other treatment options the chance to receive an investigational agent for treatment outside a clinical trial. Of note, the term EA is often used interchangeably with expanded access program (EAP). However, an EAP is a formal plan under which pre-approval access to an investigational drug is provided to a group of patients rather than to an individual patient. The rest of this discussion will focus on EA for a single patient submitted by a health care provider.

Several requirements must be met for an individual patient to receive an investigational medication via the EA pathway. The manufacturer must be willing to supply the drug, the patient’s physician (or delegate) must obtain institutional review board (IRB) approval, the physician must apply on the patient’s behalf to the FDA, and the FDA must authorize the request.² Historically, the FDA has authorized more than 99% of EA requests.³ Median response times for the FDA’s Center for Drug Evaluation and Research are less than 1 day for emergency EA requests and 4 days for nonemergency EA requests.⁴ An investigational medication accessed via EA must be solely intended for the treatment of patients. This is inherently different from a clinical trial, where use of an investigational medication is primarily for research. Further, although the process to submit an EA request has improved in recent years, there are still several steps that must be completed by the treating physician and institution to obtain approval to gain access to and use investigational medications. The first step in requesting EA is to determine whether the patient is eligible to receive an investigational medication through this pathway.

The FDA website refers the health care provider to clinicaltrials.gov to ensure there is no currently available clinical trial to which the patient can enroll. Next, the physician must contact the pharmaceutical company (also referred to as the sponsor or manufacturer) to request a letter of authorization (LOA) and formally request that the pharmaceutical company provide access to the investigational medication. To facilitate this process, the FDA made available an EA navigator tool that allows health care providers to search the FDA website for the pharmaceutical company directory to determine a contact for making this request.

Through the LOA, it is possible for the sponsor or manufacturer to grant approval to cross-reference the investigational drug or the investigational new drug (IND) application on file with the FDA. The pharmaceutical company can refuse to provide the LOA and the investigational medication, but if this occurs, the physician may contact the FDA EAP to ask for assistance with the request. Under 21CFR312.8, the FDA allows the sponsor of the IND, which may be the pharmaceutical company, the physician, or health care institution, to recover its costs for providing the investigational medication via EA. The sponsor may recover their charges through third-party payers (eg, insurance companies) or through charging the patient directly. If the patient treated under EA is to be charged for the costs associated with receiving the investigational medication, the consent form must reflect this financial obligation.^5,6

Once the pharmaceutical company agrees to provide the drug and LOA and the physician has submitted Form FDA 3926, the prescriber (or delegate) must obtain IRB approval. The IRB approval process for review of EA requests has also improved over the past several years because requests for approval no longer require the full board to convene. Instead, one member of the IRB may provide their concurrence for the request, which greatly decreases the time of the IRB submission and approval process.

In addition, the patient must be informed of the investigational nature of the treatment and the associated risks. The patient must then provide consent, most commonly written consent, although alternative methods and waivers to written consent documentation can be requested.

EA may be requested for a single patient or more than 1 patient. For single-patient access, also known as compassionate use or single-patient IND, use must be designated for emergency or nonemergency use; this determination is made by the treating physician. Single-patient emergency use is defined as a request for a patient who is not expected to live long enough for the FDA and an IRB to review a typical single-patient EA request and has a shortened FDA approval time.⁷ The process for an emergency request is described in the FDA Code of Federal Regulations Title 21 Part 312.310, which states that “if there is an emergency that requires the patient to be treated before a written submission can be made, [the] FDA may authorize the expanded access use to begin without a written submission.”⁸ In this scenario, the FDA reviewer may authorize the emergency use by telephone.

Navigating the EA process has historically been complex and required significant time, which created barriers to obtaining treatments for many patients and may still be an issue for physicians without access to a hospital with a local IRB or research program. Recently, the FDA has taken additional actions to clarify and streamline its policies regarding the EA process, including issuing guidance documents on EA, restructuring the FDA web page on EA, launching Project Facilitate (a call and information center to help with EA request submissions), simplifying the application form for single-patient requests so that form completion takes an estimated 45 minutes, and working with the Reagan-Udall Foundation to launch the Expanded Access Navigator website to help patients and physicians more easily locate relevant information about EA.⁹ Additional guidance and educational modules for navigating the process may be found on the FDA’s website, along with several resources to assist the physician with the EA process. There is also an app available, Expanded Access eRequest, which allows physicians to request nonemergency use of investigational drugs for their patients from their mobile device. This app also allows physicians to complete, sign, and submit Form FDA 3926 online to the FDA.

In addition to the already-mentioned entities (physician, FDA reviewer, manufacturer, patient, and IRB) involved in obtaining EA approval for a single patient, other parties such as an advanced practice provider (eg, nurse practitioner, physician assistant, or advanced practice pharmacist) or a clinical pharmacist also may assist by reviewing clinical trial options and eligibility and developing the brief clinical history needed to submit the EA request and Form FDA 3926. However, at the time of publication of this article, Form FDA 3926 (04/24) did not allow non-physician providers to submit an EA request, as the form requires documentation of the physician name and contact information, physician qualification statement, and physician signature documenting acceptance of the certification statement. If the institution has a clinical trials office, a regulatory associate with that office may assist the physician with submitting the required documents to the sponsor or manufacturer, to the IRB, and to the FDA. A physician who does not have access to a local IRB typically uses an independent IRB, but utilizing an outside IRB will most likely add cost to the review of EA requests.⁸

If the institution has an investigational drug service pharmacy, these pharmacists and staff may assist with ordering, receiving, preparing, dispensing, and maintaining documentation of the investigational drug supply. Keeping all involved entities up to date on the status of the request is critical to ensure there are no delays throughout the process and in treating the patient once the approval is obtained and drug is received.

Overall, significant advancements have been made to the process of requesting and obtaining EA for a single patient over the past several years. There are now many resources available to assist a physician with obtaining an investigational drug for patients who have exhausted all other treatment options via EA in a timely manner. For these reasons, EA remains a feasible and achievable pathway to access an investigational medication and in a more streamlined manner than previously available to providers.

Right to Try Act

The Right to Try Act (RTT), officially known as the Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017, was signed into law as an amendment to chapter 5 of the Federal Food, Drug, and Cosmetic Act on May 30, 2018.^9,10 This pathway allows terminally ill patients who have exhausted FDA-approved treatment options and are unable to participate in clinical trials to request access to investigational drugs or biologics upon certification by a physician that the patient meets RTT eligibility criteria.^9-11 For example, RTT eligibility criteria include that the investigational medication must be the subject of an IND application filed with the FDA and cannot be approved or licensed by the FDA for any other use; must have completed a phase 1 clinical trial; and remains under active development in clinical trials intended to support effectiveness claims in pursuit of FDA approval.^9-11

Under this legislation, eligible patients or a treating physician may contact a manufacturer or sponsor of the desired medication to request access. If a manufacturer agrees to provide the investigational medication, physician coordination and oversight are required to develop a treatment plan and obtain written informed consent from the patient or legally authorized representative. Manufacturers and sponsors must also report information to the FDA annually on which investigational agents they have allowed access to via the RTT pathway, including drug name and IND number, indication, number of doses supplied and patients treated, and any adverse clinical outcomes.11 The FDA then posts a consolidated annual summary report of RTT use on its website.^9,10

A key difference between RTT and the EA pathway, as highlighted in Table 1, is the notable absence of safety and regulatory oversight by the FDA and an IRB. For RTT requests, the FDA does not play a role.⁹ Although RTT requires patients to provide informed consent, the content of consent is not specified and IRB review is not required.⁸ Instead, the physician is responsible for ensuring a patient is eligible and for obtaining written informed consent.^8,10 Due to treatment outside of a formal, tracked process (eg, clinical trial) and lack of IRB oversight, it is difficult to find comprehensive information on the number of patients who have successfully utilized this pathway and the associated clinical outcomes.

Ultimately, as with EA, manufacturers developing investigational medications are not required to provide the agent, and if provided, they are allowed to charge the patient for the agent to recover their costs.¹⁰ Many payers will not reimburse for agents that are not FDA approved and will only cover costs of care associated with investigational medications in the context of a clinical trial.⁹ Even if a manufacturer agrees to provide an agent at no cost, there are significant financial barriers associated with administration and potential adverse effects that would need to be addressed by the patient and physician.

RTT garnered initial support among certain patient advocacy groups; however, many other patient advocacy groups along with professional organizations and drug manufacturers have voiced opposition to this pathway being made available through legislation.^12-15 Although the RTT legislation effectively created an alternative pathway for patients to seek access to investigational agents in specific circumstances, there are several limitations to its use. First, the RTT legislation does not establish any new mandates, directives, or regulations,11 so manufacturers, prescribers, dispensers, and other entities cannot be held liable for providing—or not providing—an investigational medication under this act, except in the case of misconduct or negligence.^10,11 Further, there is no obligation for a manufacturer or physician to provide or prescribe an investigational medication to a patient who requests access.⁹ And as an additional protection to the manufacturer, any clinical outcomes, including adverse effects, cannot be used to delay or negatively affect the review or approval of the investigational agent unless the outcome is critical to determining the safety profile of the agent.^10,11 Furthermore, although called RTT, this legislation does not guarantee access to investigational medications as the title may imply; rather, patients merely gain the right to request access to them.¹¹

Lastly, and perhaps most importantly, the RTT states, “[The Act] will not, and cannot, create a cure or effective therapy where none exists.”¹¹ This statement serves to bring context to an often grave situation for patients and caregivers who have exhausted all possible treatment options and highlights the incredibly important need for ongoing research.

Off-Label Use

The term off-label is defined as a medication used to treat a condition for which it has not received FDA approval and can apply to the use of an FDA-approved medication in a patient population being provided with a dose or dosage form that is not approved.^12-17 However, using a drug with little to no scientific evidence has been described as off-evidence use, distinguishing it from off-label use, which can be supported by scientific evidence.¹⁷ Although this may sound alarming to the public, off-label use is quite common, especially in oncology, pediatric, and palliative care settings where many therapeutic options may not have formal FDA approval and have limited or anecdotal evidence to support their use. As such, they may still be included in compendia and treatment guidelines despite their lack of approval for a condition or indication. A literature review found that between 13% and 71% of adult patients with cancer received a minimum of 1 off-label chemotherapy drug and that off-label use unsupported by guidelines or compendia ranged from 7% to 31%.¹⁸

Although the FDA prohibits manufacturers from marketing or promoting off-label use of products, there is limited guidance on how to address prescriber requests for off-label use. General recommendations require health care providers to assess whether there is sufficient evidence to justify use (risks vs benefits), to ask for additional information and research when evidence is lacking, and to inform patients about the uncertainties and associated costs. Systematically answering a preset list of questions may help the prescriber with the assessment process when considering an off-label treatment option for a patient with cancer (Box). After evaluating the evidence and patient-specific factors leading to consideration of off-label use, the prescriber needs to inform the patient about the limited data, any uncertainties, and the financial implications. Together the patient and prescriber should make the joint decision as to whether the patient should move forward in seeking off-label treatment if the prescriber agrees it is in the best interest of the patient to use this treatment. Ultimately, the final decision may lie with the health care practice or the insurance. Some institutional policies limit or prohibit the use of off-label treatment depending upon the degree of potential risk based on available evidence in the literature. If the use of an off-label treatment is not supported by the institution through the commercial pathway, then the provider may need to seek use through an EA or clinical trial. Third-party payers may deny insurance authorization for off-label treatment based on available evidence. Depending on the cost of the treatment, the patient may not be able to afford out-of-pocket payment and thus may need to pursue a different therapy.

Even though the effort to obtain off-label treatment for a patient is usually the responsibility of the prescriber, the patient may be the primary driver of the request. This is often the case with a patient who is terminally ill and has a progressive or unresponsive disease. This may also be seen in the targeted therapy or precision medicine space, where a patient may have a driver mutation identified by next-generation sequencing that may make them a candidate based on drug mechanism of action for a treatment that is not yet FDA approved for the tumor type. The provider may consider extrapolating available data to this patient, but the dosing or frequency may not yet be established.

There is a fine line between research and clinical practice because they intertwine throughout most spaces that perform research tasks alongside patient care. The terms research and investigational are often used to denote a practice that is deviating from the standard. The Belmont Report recommends that any activity that includes an element of research be reviewed for human participants’ protection.¹⁹ Notably within The Belmont Report, the term practice implies treatment of an individual, even if this deviates from the standard, whereas the term research means a hypothesis is being tested in a formal setting involving more than 1 participant, which may help contribute to generalizable knowledge. However, deviating from the standard of care, even in a way that is denoted as investigational, does not in and of itself mean that the deviation is research.¹⁹

It is the responsibility of the medical community to ensure that unusual, radically new therapies are made the focus of formal research as soon as possible to determine whether they are safe and effective, and this includes utilizing medications off-label in novel ways for which there is insufficient evidence of safety and efficacy.

Dresser and Frader examine the ethics surrounding the use of an off-label medication without sound evidence of safety and/or efficacy, noting that although off-label prescribing can potentially provide the best option for an individual patient, many professional organizations, such as the American Medical Association and the American Academy of Pediatrics, support off-label use only when it is based on “sound scientific evidence” and done “in the best interest of the patient.”²⁰

Therefore, according to Dresser and Frader, there are 2 ethical considerations for off-label prescribing: (1) the evaluation of existing evidence for this particular use and (2) the collection of information and the conduction of research when there is inadequate evidence. Importantly, Dresser and Frader explain that the use of off-label prescribing in the face of insubstantial evidence exposes patients to potentially ineffective and harmful treatment.¹⁹

While there are no official guidelines or regulations to address off-label prescribing for the health care provider, current regulations apply only to the manufacturers.²¹ Prescribers can exercise professional judgment to prescribe off-label medications at their will. However, only when the provider or patient requests information for off-label usage directly from the manufacturer can the manufacturer respond. Outside of a public inquiry to the manufacturer, the manufacturer is prohibited from promoting the use of medications for off-label indications due to FDA policy.

Health care organizations have different approaches to handling off-label prescribing, which may include a local IRB or scientific research committee review, a pharmacy and therapeutics committee review, or other reviews governed by institutional or payer policies; in some settings, however, there is no process at all. Additional considerations include specific documentation in the medical record of the education provided to the patient, a signed informed consent form that contains information regarding potential adverse outcomes, and a statement of the patient’s understanding that this is pursued in their best interest or at their request.

Conclusion

Although FDA-approved medications and clinical trials are the foundation for treating patients, alternatives such as EA, RTT, and off-label medications are paramount to broadening treatment options for patients, especially for those with limited options.

Each pathway is unique in its requirements, role, and complexities. For example, EA requires manufacturer approval and both safety and regulatory oversight by an IRB and the FDA, whereas prescribing medications through the RTT and off-label pathways is subject to manufacturer and insurance approval, respectively, and does not involve the IRB or FDA, respectively.

Furthermore, any eligible, authorized, licensed prescriber may prescribe off-label treatment in accordance with local, state, and federal regulations. However, all 3 pathways are governed by different regulations and laws that prescribers need to be aware of, so it is important to leverage the resources available through local pharmacists, clinical trials offices, the Reagan-Udall Foundation, Project Facilitate, FDA websites, and institutional regulatory offices to successfully navigate these pathways (Table 2).^10,11,22-25

Because there is no guarantee that the manufacturers will provide the agents for free to the patient or institution for use via the EA and RTT pathways, the health care team needs to manage patient expectations from the onset through a clear description of the pathway selected.

Navigating access to investigational or off-label medications for patients who have exhausted all other treatment options can be challenging. To best support patients, health care providers and institutions must understand not only what alternative treatment pathways are available for accessing medications outside FDA approval but also the steps required, and the limitations associated with each pathway.

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Authors have declared no potential conflicts of interest relevant to this topic. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of their institutions.

Human Subjects Protection Statement: Institutional review board approval was not obtained due to the nature of this article and lack of enrollment of human or other participants.