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Oversight of Right‐to‐Try and Expanded Access Requests for Off‐Trial Access to Investigational Drugs

Carolyn Riley Chapman

Faculty affiliate of the Division of Medical Ethics in the Department of Population Health in the NYU School of Medicine at NYU Langone Health

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Jared Eckman

Worked on this article as an intern in the Division of Medical Ethics in the Department of Population Health at NYU School of Medicine at NYU Langone Health and is currently pursuing an MD as well as an MA in bioethics at Emory School of Medicine

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Alison S. Bateman‐House

Assistant professor in the Division of Medical Ethics in the Department of Population Health in the NYU School of Medicine at NYU Langone Health

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First published: 22 January 2020

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ABSTRACT

For decades, the U.S. Food and Drug Administration (FDA) has provided an “expanded access” pathway that allows patients who meet qualifying conditions to gain access outside a clinical trial to an investigational medical product being tested to see if it is safe and effective for a specific use. The Right to Try (RTT) Act, enacted in 2018, created a second mechanism for off‐trial, or non‐trial, access to investigational drugs. In contrast to the expanded access pathway, the federal RTT pathway does not require the involvement of the FDA or an institutional review board (IRB). Given that physicians, drug manufacturers, and medical institutions now have a choice whether to assist individual patients through the expanded access or the federal RTT pathway, we review the differences between these options and discuss the benefits and burdens of IRB involvement in requests to access interventions through the pathways. We also suggest ways in which IRB oversight may be further improved.

On January 8, 2019, the University of California, Irvine (UCI), and the biopharmaceutical company ERC‐USA (Epitopoietic Research Corporation) announced that, in accordance with the 2017 federal Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try (RTT) Act (signed into law in May 2018), they granted a patient off‐trial, or non‐trial, access to an investigational drug that the company was testing for safety and efficacy in a phase II clinical trial.1 The federal RTT law was the culmination of a national campaign spearheaded by the Goldwater Institute, a libertarian organization, to get the states and Congress to pass laws giving patients with life‐threatening illnesses access outside of clinical trials to investigational drugs that have not been approved by the U.S. Food and Drug Administration (FDA). By the time the federal RTT law went into effect, all but ten states (Alaska, Delaware, Hawaii, Kansas, Massachusetts, New Jersey, New Mexico, New York, Rhode Island, and Vermont) had enacted their own RTT laws. Alaska became the 41st state to enact right‐to‐try legislation in July 2018.

The patient at UCI reportedly was the first to use the federal RTT pathway.2 A month after the announcement by UCI and ERC‐USA, the Goldwater Institute announced that a person with amyotrophic lateral sclerosis (ALS) also relied on the federal RTT law to gain access to BrainStorm Cell Therapeutics’ investigational product, NurOwn.3 The treating physician in the UCI case stated that this pathway “may be the only alternative” for some patients who do not meet eligibility criteria to enroll in clinical trials.4 However, the federal RTT pathway is actually one of two mechanisms for patients to request off‐trial access to unapproved investigational medical products (often referred to as “compassionate use”). For decades, the FDA has offered an “expanded access” pathway through which a physician, on behalf of a qualifying patient, can request access to an investigational drug, biologic, or medical device outside of a clinical trial.5 Now that there are two pathways for off‐trial access to investigational drugs and biologics, it is critical for physicians, drug manufacturers, medical institutions, and other relevant stakeholders to understand their differences. Furthermore, and in light of a 2016 federal law requiring companies to make public their expanded access policies once an investigational drug begins phase II of clinical testing, medical institutions and drug manufacturers should develop processes for reviewing off‐trial access requests and for determining when and if access should be provided under either the federal RTT law or expanded access.6

Here, we compare the two pathways and discuss the interplay between the federal RTT law and those enacted by the states. We explore three main options available to drug manufacturers and medical institutions that wish to support a patient's request for off‐trial access to an investigational drug: require use of the expanded access pathway, require reliance on the federal RTT pathway, or permit either approach. Along with various other stakeholders, we recommend the expanded access pathway over the federal RTT approach.7 We also suggest that drug manufacturers and medical institutions that agree to support a patient who wants to use the federal RTT pathway carefully consider the benefits and burdens of requiring third‐party review and approval of such RTT requests. Although such oversight may be viewed as contradicting the intent of the federal RTT law, which aimed to reduce the regulatory and oversight burden of requests, there are significant ethical justifications for insisting on third‐party review of innovative medical practice,8 including compassionate use mechanisms like the RTT and expanded access pathways.9

The Two Pathways

The federal RTT law established a pathway solely for individual patients who want off‐trial access to investigational drugs (including biologics), whereas the expanded access approach can be used for either an individual patient or cohorts of similar patients who want access to investigational drugs, biologics, or devices. We limit our analysis concerning the expanded access pathway to single‐patient expanded access to investigational drugs, which is the applicable comparison to the federal RTT pathway.

To qualify for single‐patient expanded access, a patient must have an immediately life‐threatening or serious disease or condition and have no other treatment or research options for it (including eligibility for clinical trials). To qualify for the federal RTT pathway, a patient must have a life‐threatening disease or condition and have exhausted approved treatment options, and must not be eligible for a clinical trial testing the investigational drug of interest; however, the patient may be eligible for a clinical trial testing a different drug for the disease or condition.

There are significant ethical justifications for insisting on third‐party review of innovative medical practice, including compassionate use mechanisms like the right‐to‐try and expanded access pathways.

The expanded access pathway to off‐trial investigational medical products involves five entities with defined roles. After discussions and shared decision‐making with the patient or their surrogate, the physician sponsors a patient's request to the product manufacturer for off‐trial access to its product. After receiving the request, the company decides whether it is willing to grant access. If so, the company may support the physician in submitting the request to the FDA. The FDA applies a risk‐benefit analysis in reviewing the expanded access request. If the FDA allows the request to proceed and does not consider it to be an emergency, an institutional review board (IRB) or its designated member (usually at the treating medical institution) reviews the request and its accompanying informed consent form. If the request is deemed an emergency, the request requires FDA permission to proceed, but an IRB does not need to proactively review it; however, an IRB must be informed within five days of the emergency use. If a patient is granted off‐trial access to the investigational product, the physician is responsible for reporting to the IRB, the product developer, and the FDA any serious and unexpected adverse events that occur from its use. Although the FDA's expanded access pathway has been available to patients for decades, product developers have many reasons to sometimes deny requests for off‐trial access to their investigational medical products,10 and there has been confusion about the steps and sequence of the expanded access process.11

The federal RTT pathway is similar to the expanded access approach, with the exception that the FDA and an IRB are not required to approve the request for access to an investigational drug. The treating physician must certify that the patient has exhausted all treatment options and is unable to participate in an ongoing clinical trial testing the drug. The Goldwater Institute and other RTT advocates insisted that the removal of “bureaucratic hurdles” such as FDA and IRB approval requirements would help patients gain faster access to investigational drugs and give them control over their care.12 Many bioethicists, clinicians, and patient advocacy organizations opposed the federal RTT law, arguing that the FDA was not an obstacle to patients’ gaining access to investigational drugs through the existing expanded access pathway.13 RTT critics stressed that the FDA sometimes suggests modifications to treatment plans to maximize the chance of benefit and minimize the risk of harm to patients14 and that removing the agency from the process could harm patients.15 They were also concerned that access through the RTT pathway could divert patients from clinical trials16 and that some companies or doctors might use this pathway to sell investigational drugs for profit.17 Contention about the merits of expanded access versus the federal RTT pathway substantively revolved around how single‐patient access to an investigational drug should be mediated, not about whether such access is desirable or possible. The debate largely focused on the FDA's role for each pathway;18 however, the two pathways differ in other significant ways, and opponents were also concerned about eliminating IRB oversight (see table 1).

Table 1. Key Differences between Single‐Patient Expanded Access and Right‐to‐Try Pathways
Expanded access Right to try
Patient eligibility Immediately life‐threatening or serious disease or condition Life‐threatening disease or condition
No other treatment or research options (including eligibility for clinical trials) No treatment options; not eligible for clinical trial of the investigational drug or biologic of interest
Required support Treating physician Treating physician
Manufacturer or sponsor Manufacturer or sponsor
FDA
IRB
Drug or biologic eligibility No restrictions Completed a phase I trial and in current clinical development
Charging regulations This pathway allows charging only for direct costs. Documentation must be submitted to the FDA. This pathway allows charging only for direct costs; however, the requirements for documentation are unclear.
Informed consent Requirements in the Code of Federal Regulations must be met. Written consent is required, but specific requirements are unclear.

Both pathways allow companies to charge patients for the investigational drug—but only for direct costs. ERC‐USA did not charge the UCI patient for its investigational vaccine against glioblastoma.19 Historically, most companies that have provided their products to patients in the United States via the expanded access pathway have not required patients to pay for the products. Without the FDA directly involved in the federal RTT pathway, there is confusion about how the limits on charging will be enforced.20 The federal RTT law specifically states that clinical trial sponsors must comply with 312.8(d)(1) of the Code of Federal Regulations (which limits charging trial participants for the investigational drug only to recovery of direct costs), but does not refer to 312.8(d)(3), which states that sponsors must provide supporting documentation.21 While the RTT law does not require FDA review or approval of access requests that proceed through this pathway, it is important to point out that the law's provisions were inserted into the U.S. Federal Food Drug and Cosmetic Act, which means that the statutory authority for enforcement of RTT rests with the FDA.

Options for Companies and Medical Institutions

Drug manufacturers and medical institutions can support patients through either pathway without preference, or they may compel the use of one pathway or another. The federal RTT pathway imposes fewer burdens on physicians, drug manufacturers, and institutions compared to the expanded access approach and offers substantial liability protections. If companies and institutions support requests through the federal RTT pathway, they will need to follow the federal regulations; however, a state RTT law may also apply. If state and federal law conflict, federal law preempts state law, as per the supremacy clause in the U.S. Constitution. However, if the state law contains provisions above and beyond those in the federal law, those would likely still apply, unless they undermine the general purposes of the federal law. Since the federal RTT law does not clarify how the preemption will be operationalized, specific legal requirements will need to be evaluated on a state‐by‐state and case‐by‐case basis.22 As an example, since California's RTT law requires IRB review of the informed consent form and ERC's RTT policy explicitly states that it will comply with both federal and state RTT laws and that it requires ethics approval and oversight for all RTT cases, it is likely that an IRB was involved in reviewing the RTT request at UCI.23 California's RTT law also requires that a consulting physician confirm the patient's diagnosis and prognosis and

Whether companies and medical institutions are neutral about the two pathways, prefer one over another, or support only one pathway, they are ethically obligated to be transparent and communicative with physicians and their patients seeking off‐trial access to investigational drugs.

recommend access to the investigational product. California is the only state to require IRB review of the consent form in its RTT law. Indiana's RTT law is unique in requiring approval “by the governing board of the hospital or by a committee of the hospital authorized by the governing board to approve the types of experimental or nonconventional medical treatments that may be provided” on an inpatient or outpatient basis at state department‐licensed hospitals.24

If companies and institutions agree to requests under the federal RTT pathway, they do not have to require any additional oversight mechanisms above and beyond the requirements of federal and state law. Companies may simply rely on their internal review of a physician‐sponsored request, and institutions may feel that the treating clinician's judgment is sufficient. The trade‐off is that each of these parties may act out of self‐interest or have knowledge limitations. Therefore, the patient may not be fully protected or informed. The physician, for example, is charged with assuring that the patient has no other therapeutic or research options; however, physicians may not be fully knowledgeable about all ongoing clinical trials for which the patient may be eligible, particularly if they have no consultation with the FDA. There are significant risks to using investigational drugs, and the patient may suffer injury or even die—clearly undesirable outcomes. Although the company and institution would be protected from liability via the federal RTT law, they may still suffer reputational damage should unexpected harm occur, especially if there were other options available to the patient or if the physician was underqualified, had conflicts of interest in the case, or was unprepared for the foreseeable side effects of the drug. For the expanded access pathway, these are all issues that the FDA and an IRB should be examining, although there is limited insight into how often or well they do so.

Even if pressured, companies and institutions are under no obligation to provide off‐trial access to investigational drugs under the federal RTT pathway. The federal RTT law specifically states that no entities may be liable for not providing access to an investigational drug. Companies and institutions may instead preferentially guide patients toward the expanded access pathway. For example, Janssen Pharmaceutical's preapproval access policy states, “We support these requests through our established review and evaluation processes, which includes [sic.] independent review by the FDA to assure full consideration of available safety data of which the FDA may be uniquely aware.”25 This statement suggests that Janssen will use the expanded access pathway. Likewise, Pfizer states that its “leading policy principle with respect to Federal Right to Try Legislation is to protect the FDA oversight of expanded access, safety, and the integrity of clinical trials.”26 As with the federal RTT law, companies and institutions are not required by law or obligated to provide off‐trial access to investigational drugs, biologics, or devices under the expanded access pathway.

Although the expanded access pathway poses additional administrative burdens, this pathway ensures better safeguards for patients, as the FDA reviews all requests and either an IRB or its designated member must review nonemergency requests. Review by the FDA is not a “rubber stamp” approval, especially given the agency's access to confidential data and knowledge about other drugs in the same class as the investigational product of interest. In addition to suggesting modifications to some treatment plans, the agency has not allowed patients to gain access to investigational drugs via the expanded access pathway in situations in which the treatment proposal involved “unsafe dosing, demonstrated lack of efficacy for intended use, [or] availability of adequate alternative therapies.”27 Likewise, data from an early 2018 survey of IRB professionals suggest that IRBs do not approve all expanded access requests they review; a few respondents noted that their IRB had declined to approve requests as a result of concerns about the risk‐benefit ratio of the investigational product and/or the existence of other therapeutic or research options.28 Patients may want access to investigational drugs with minimal red tape, but their autonomy is constrained by the interests and obligations of other parties—specifically, clinicians, drug manufacturers, and medical institutions involved in the request for access. Some or all of these other stakeholders may feel—and those with a fiduciary relationship to the patient should feel—an ethical obligation to ensure that the use of an investigational drug is in the patient's best interest. There are, indeed, robust justifications for requiring third‐party review of innovative clinical practice in which physicians deviate from routine clinical care and from approved research protocols.29 Physicians may feel pressure to provide an option for the patient and may overestimate the chance that an investigational drug will help, or underestimate its potential to do harm. They may even have financial interests in the drug or in the provision of care associated with its delivery.

One promising development intended to ease the administrative burden associated with the expanded access pathway is the FDA's new initiative to make the process more effective, equitable, and transparent.30 The pilot program, called Project Facilitate, has launched a call center focused on helping oncology health care providers or regulatory professionals navigate the expanded access process.31 The initiative is meant to complement information provided in the Reagan‐Udall Expanded Access Navigator, a several‐years‐old online resource intended to guide patients and physicians through this pathway. The Navigator also hosts a voluntary list of companies that may provide their investigational products via expanded access; this accords with provisions in the 21st Century Cures Act of 2016 that require companies to publicize their expanded access policies relating to their investigational drugs after the initiation of phase II testing.

For patients with life‐threatening disease who have no other treatment options and are ineligible for clinical trials, giving them easier and more efficient access to investigational drugs is a worthy goal. The federal RTT law seeks to do so by removing the FDA and IRBs from the process. However, questions remain about whether physicians have enough knowledge about ongoing clinical trials to advise their patients about their options and whether, without the IRB's role, patients would be fully informed and protected from avoidable harm. To best meet the goals of the RTT law, there are strong reasons to work within the confines of the long‐standing expanded access program, but we acknowledge that there is still room to improve the process.

A Potential Middle Ground?

Legal experts have stated that drug manufacturers and medical institutions “may voluntarily add requirements to the provision of investigational drugs through the ‘right to try’ pathway, regardless of the existing regulatory framework.”32 As an example, in the UCI case, ERC‐USA exceeded the requirements of both the federal and California RTT laws by notifying and receiving acknowledgment from the FDA that it planned to treat a patient under the RTT pathway.33 Some may view additional institutional or state RTT law requirements to be in conflict with the intent of the federal RTT law and thus vulnerable to a preemption challenge. After all, the federal RTT law was expressly aimed at reducing bureaucratic hurdles for patients with life‐threatening diseases who are seeking to access investigational drugs. But others may judge additional oversight, aimed to protect patients, to be consistent with the federal RTT law. Because the law does not oblige companies, physicians, or medical institutions to provide an investigational drug to a patient under any circumstances, it seems consistent that they can specify the circumstances of such provision. Courts may hold that state laws “supplement and explicate the way in which this activity (the provision of investigational drugs outside of FDA's purview) can occur in a given jurisdiction, rather than serving to frustrate Congress’ intent in making the ‘right to try’ pathway available.”34 However, some aspects of state laws may conflict with the federal law; making determinations in these cases will likely require careful and expert legal analysis.35

If medical institutions decide to impose additional oversight for requests under the federal RTT pathway, there are different mechanisms to consider. One possibility would be to require an internal clinical ethics consultation about requests if a clinical ethics service is available. With most hospitals now having clinical ethics services, this may be a reasonable solution because preapproval off‐trial access can be classified as a clinical endeavor since its goal is to provide therapeutic benefit to a patient, not to create generalizable knowledge, as is the case with research. Alternatively, a medical institution may set up a de novo committee to review and perhaps facilitate RTT requests.

Another possibility is for medical institutions to require a designated member of an IRB to review requests under the federal RTT pathway. This would be consistent with the review process for requests under the expanded access pathway.36 The FDA and others have repeatedly affirmed IRB review as important for expanded access requests because of the experimental nature of the treatments and the vulnerability of the patients.37 IRB members understand the risks involved with investigational products and are experts on informed consent. Over three‐quarters (78.3%) of IRB professionals who completed the early 2018 survey agreed or strongly agreed that it is important for a designated IRB member to review nonemergency expanded access requests; the needs to ensure informed consent and to protect the rights and welfare of the patient were rated as the most important reasons.38 However, there has been long‐standing debate about the necessity of IRB review for expanded access requests.39 IRBs are notoriously overburdened, and reviewing requests for off‐trial access to an investigational drug to be used in a clinical, rather than a research, context may be outside the IRB's scope and expertise.40 The risk‐benefit assessment of an expanded access or RTT request is ultimately a clinical judgment on what is best for a particular patient, which is quite different from a risk‐benefit analysis of research protocols. Although IRB members can check the robustness of consent forms if they are provided with the requisite information, it seems unlikely that they would be qualified to oversee the sponsoring physician's clinical judgment. Further, given that the RTT movement expressly aimed to eliminate IRBs from the review and approval process, requiring this involvement might bring challenges from the spheres of public relations or law.

Yet there are very real concerns that patients, physicians, and even company representatives can fall under the sway of the therapeutic misconception and that physicians might have conflicts of interest if, for example, they hope to publish a case report of a novel drug or if they have financial ties to the company developing the drug. Therefore, another possibility is for institutions and companies to require another physician with appropriate expertise to review and provide a second opinion for requests under the federal RTT law. California's state RTT law requires that, in addition to the treating physician, a second consulting physician must also recommend that the patient be treated with the investigational drug and attest that the patient meets the eligibility criteria of the state law. The RTT laws of Arizona, Florida, Ohio, Oregon, and Virginia contain language requiring that a second physician confirm the diagnosis and/or prognosis of the patient, but these laws do not require that the second physician agree with the decision to use the investigational drug. Having a physician with appropriate knowledge of the disease review requests under the federal RTT law could help clarify whether the investigational drug has sufficient potential benefits to justify its risks and could increase the likelihood that a patient is informed of all alternative options, including clinical trials, palliative care, and off‐label use of FDA‐approved drugs. Despite the benefits of a second physician's opinion, however, legal, logistical, and financial barriers may diminish the desirability or practicality of making this a requirement. At the very least, patients could be encouraged by advocacy groups to consider seeking a second clinical opinion, even if it is not required by institutions.

Again, while these additional oversight mechanisms layered onto the federal RTT pathway may protect and benefit patients, the use of such mechanisms might be challenged with the claim that they go against the intent of the federal law. In light of this possibility, companies and medical institutions that would prefer some form of third‐party review of requests initiated through the federal RTT pathway may instead opt to prioritize the expanded access pathway.

Recommendations for Moving Forward

To minimize administrative burdens on all parties involved with a single‐patient request, it is important to clarify best practices and improve processes.41 Although the expanded access and federal RTT pathways should be options of last resort—with most access to investigational drugs occurring in the context of a clinical trial—companies and medical institutions must proactively formulate their policies and recommendations so that they can respond to expanded access and RTT requests in a timely manner and guide physicians and patients appropriately.42 Whether they are neutral about the two pathways, prefer one over another, or support only one pathway, companies and medical institutions are ethically obligated to be transparent and communicative with physicians and their patients seeking off‐trial access to investigational drugs. As both pathways typically involve an agreement between the medical institution and the company supplying the investigational agent,43 physicians should understand whom to contact to initiate that process. One medical team that facilitated an expanded access request stresses the importance of identifying key personnel, including pharmacy and finance administrators, and their responsibilities, as well as the development of written protocols that detail the institution's protocols and processes.44 If nothing else, passage of the federal RTT law demonstrates widespread support for allowing patients access to investigational drugs for therapeutic purposes, in certain circumstances. Yet the logistical and administrative processes associated with providing such access are not trivial.

Perhaps Project Facilitate, which is being piloted in oncology, will eventually help minimize the burden for all stakeholders involved with expanded access requests. IRBs can also play a role in educating clinicians about how expanded access requests are to proceed. Even with this well‐established pathway, a recent research report commissioned by the FDA found that there is confusion about the sequence of steps physicians must take in requesting that their patient get access to an investigational drug.45 Ironically, a graphic in the report—written by a consulting company—describes FDA and IRB review as occurring in parallel. This approach is not optimal. When conducting a review of an expanded access request, many IRBs require a letter from the FDA stating that the agency is allowing the request to proceed.46 In fact, before approving a consent form, it is prudent for an IRB to review correspondence from the FDA because the agency recommends changes to the treatment plan in 11% of cases.47 Obviously, if medical institutions agree to support a patient's access request via the federal RTT pathway but require oversight by their IRBs, then the IRB member will need to conduct the review without the benefit of information from the FDA.

Additionally, while the use of a single IRB member to review expanded access requests has been well received,48 members with this responsibility must be adequately supported and educated about both access pathways. To clarify and standardize review, a checklist of essential considerations should be developed for the single reviewers. Perhaps the federal Office for Human Research Protections could facilitate this effort, as its mission includes education and outreach. Another possibility is for the FDA to provide guidance to IRBs. The early 2018 survey of IRB professionals experienced with the expanded access pathway found overlaps but not complete concordance in what was considered when reviewing an expanded access request. Although every respondent indicated that their IRB required an informed consent form, the physician's professional resume was required by only 35.9% of respondents.49 Some IRBs require a letter from a physician not involved in the patient's care, which may be extremely valuable if the IRB reviewer is not familiar with therapeutic or research options for the patient.50 Federal regulations governing research with humans (45 C.F.R. 46.107[e] and 21 C.F.R. 56.107[f]) state that an IRB may invite individuals with specific expertise to assist with reviews of research protocols and accompanying documents. Despite the consistent requirement for informed consent forms, these forms themselves likely vary significantly among institutions.

Standardizing the IRB submission process would simplify the single IRB reviewer's task and increase the rigor of the review process. Although, by design, IRBs are given great flexibility to fulfill the federal requirements,51 some coordination at the national level would likely help physicians navigate a patient's request. It was recently reported that one physician wrote a “10‐page research protocol and a five‐page consent form, both from scratch,” to support a time‐sensitive expanded access request for two infants with Menkes disease.52 While it is understandable that IRBs need enough information about the treatment plan to approve a patient's request, clinicians who do not normally perform research or interact with IRBs may be intimidated by submission requirements. Having a standardized approach would be useful, particularly if the FDA, drug manufacturers, medical institutions, and IRBs can all direct physicians who are assisting their patients with the expanded access and federal RTT pathways to the same guidance or instructions, especially when the request is time sensitive.

Template consent forms for each access pathway should also be developed and shared, such that the application burden is minimized and best practices are widely adopted. The consent form should address what a reasonable person would want to know. While details will vary from case to case, templates must state that the treatment option is experimental and lacks FDA approval. Safety and effectiveness information, to the extent that this is known, should be provided by the company developing the drug. Potential risks and benefits, as well as what, if any, data will be collected and how it will be shared should be communicated to the patient. Both the steps involved in administering the investigational drug and any conflicts of interest with the treating physician should also be included. Alternatives should be specified. To qualify for expanded access, patients should not be eligible for any clinical trials. RTT requires only that patients not be eligible for trials with the desired investigational drug, meaning that they may be eligible for clinical trials testing other investigational drugs; in such RTT cases, patients should be informed of other relevant clinical trials for which they may qualify. For both pathways, the template consent form should describe additional alternative options—including off‐label use of approved drugs and palliative care—and the cost of the investigational drug and any financial risks if patients have to bear those costs. For example, in some states, patients may lose hospice or in‐home health care coverage or health insurance if they proceed via the RTT pathway, a situation that should be explained in the consent process.53 The consent form should also convey “statutory limitations on the liability of a sponsor, manufacturer, prescriber, dispenser, and ‘other individual entity’.”54

The Need for Advance planning

With the recent announcements that two patients received access to investigational products outside of a clinical trial in accordance with the federal RTT law, awareness of and interest in the RTT pathway may increase. Institutions and drug manufacturers should establish and communicate clear procedures for responding to patients who request off‐trial access to investigational drugs—whether those requests are made through the expanded access or federal RTT pathway. As the UCI case demonstrates, these requests will be governed by a web of rules, regulations, and policies: in the case of expanded access, federal and institutional; in the case of RTT, federal, possibly state, and possibly institutional. Those who wish to support patients in their pursuit of off‐trial access to investigational drugs will face choices: do they guide patients through the expanded access or RTT pathway? We believe the expanded access pathway, as compared to the RTT pathway, provides more protections for patients and that these are valuable enough to justify its additional steps. Still, improvements can be made to the expanded access pathway to make it as quick and easy as possible; hopefully, Project Facilitate will help in this regard. Some medical institutions and companies may adopt policies on RTT requests that impose additional requirements, such as a clinical ethics consultation, review by an IRB member, or a second physician's opinion. Although oversight by neutral entities may give stakeholders comfort about the appropriateness of specific requests, these requirements may be vulnerable to public relations or legal challenges. Going forward, given multiple choices and options, companies and medical institutions must each determine how much oversight is “just right” when a patient requests off‐trial access to an investigational drug.

ACKNOWLEDGMENT

We thank Lindsay McNair for feedback and comments, Christopher Robertson for discussion about the interplay between the federal and state RTT laws, and Lisa Kearns for research assistance on state RTT laws.

DISCLAIMER

This essay is intended only for informational and educational purposes and should not be construed as, nor relied upon for, legal advice.

DISCLOSURE

Carolyn Chapman served from 2017–2019 as the deputy chair of the CompAC Infectious Disease committee, one of the Compassionate Use Advisory Committees (CompAC). CompAC is comprised of external expert panels of physicians, bioethicists, and patient representatives formed by the NYU School of Medicine in collaboration with Janssen Pharmaceuticals. CompAC advises Janssen about requests for compassionate use of (expanded access to) its investigational medicines. NYU receives administrative funding from Janssen to facilitate CompAC; money goes to the Division of Medical Ethics to support committee infrastructure. Chapman's salary was partially funded by this support. The Division of Medical Ethics also has a grant from WIRB/WCG to provide ethics education as part of an international research ethics fellows program. Chapman is the coordinator of the NYU component of this program. She is compensated for this work. She has also provided paid advisory services to GE2P2 Advisory Services as an independent contractor.

Alison Bateman‐House serves as an unpaid chair and an unpaid committee member for CompAC. She is an associate fellow of the GE2P2 Global Foundation and a member of its Independent Bioethics Advisory Committee (IBAC). IBAC provides bioethical consultative services to commercial and other biopharma organizations on clinical trials, expanded access programs for investigational medicines and therapies, and in other areas. Bateman‐House has accepted funds to cover travel expenses from the American Association for Cancer Research, Biogen, the European Organization for the Research and Treatment of Cancer, Johnson & Johnson, and the Reagan‐Udall Foundation for the FDA and speaking fees from the Amyloidosis Research Consortium and the Sturge‐Weber Foundation. She receives payment for work on a data safety monitoring committee for a clinical trial sponsored by the National Eye Institute. She has served as an unpaid advisor to numerous pharmaceutical and biotech companies, patient advocacy groups, and health policy organizations with regard to preapproval access to investigational medical products.

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