Most often, patients in the United States access unapproved — "investigational" — drugs, devices, or vaccines by enrolling in a clinical trial. "Compassionate use," "expanded access," and "Right to Try" refer specifically to access to investigational products outside of clinical trials, or nontrial preapproval access. expanded access and Right to Try refer to specific pathways through which patients, via their physicians, may seek nontrial preapproval access. Because Right to Try is little used, it will not be discussed further here. This explainer focuses on expanded access for tecovirimat (TPOXX) for treatment of monkeypox.
Clinical trials are research, intended primarily to obtain generalizable data that serve the social good of understanding medical conditions and how to treat or prevent them. This does not mean that patients cannot benefit from clinical trials (they can) nor does it mean that patients do not participate in clinical trials in hopes of personal medical benefit (some do). But it does mean that clinical trials are held to the standards and regulations of human-subjects research, including oversight of the research by entities other than the researchers.
In contrast, expanded access is considered medical treatment, albeit with an unproven intervention. As the intervention is unproven, the risks and benefits of its use are unknown, requiring explicit informed consent, similar to what would occur in a clinical trial. This heightened uncertainty also results in oversight by entities (institutional review boards and the US Food and Drug Administration [FDA]) that typically have no direct role in patient care. As a result, expanded access can be confused with research.
However, the US regulations are very clear that expanded access involves the use of investigational products for the treatment of or monitoring and diagnostic use of patients — in other words, that the investigational product is being used for treatment, not research, because the primary intent of using it is to benefit the patient, not to collect generalizable data.
In most instances of expanded access, a physician treating a patient determines that there are no FDA-approved treatments available for use either because none exist or because they were already tried. The physician then decides that a particular investigational product is more likely to be beneficial to the patient than harmful and decides to try to obtain access to that product.
The physician must determine that the patient is not eligible for clinical trials of the product: If they have the opportunity to participate in a clinical trial, they are not eligible for expanded access. The US federal regulations require that expanded access be limited to those who have no opportunity to participate in a clinical trial; trials need prioritization because they answer research questions, including about the safety and efficacy of the investigational product, which cannot be answered in a reliable way through monitoring treatment use of the product.
After determining that there is no clinical trial opportunity available and that the patient is a candidate for expanded access, the physician then reaches out to the sponsor (the entity developing the product, often a biopharmaceutical company) to request access. There is no requirement that such access be granted; if it is, the sponsor can decide whether to grant it on a case-by-case basis or to open an expanded-access program to treat multiple patients. Oversight bodies called Institutional Review Boards (IRBs) are also involved to ensure adequate informed consent of the patients receiving unproven interventions as is the FDA to ensure that the use of the product is as safe as possible.
The TPOXX (tecovirimat) for treatment of monkeypox expanded-access program departs a bit from this typical scenario. First, TPOXX is FDA-approved for treating smallpox; as such, it is considered "investigational" because it is being used for an indication for which it was not approved rather than because it is unapproved. This is a thorny issue because US physicians are permitted to prescribe products that are FDA-approved for a certain indication for another reason with no requirement for special oversight. Physicians frequently take advantage of that permission.
As such, something that routinely happens via "off-label use" in this context requires use of the expanded access provision. This is almost certainly because the FDA approval of TPOXX came with a unique stipulation: It could be sold only to the US's Strategic National Stockpile, supplies maintained by the US Department of Health and Human Services (DHHS) in case of public health emergencies.
DHHS, in turn, left it to the US Centers for Disease Control and Prevention (CDC) to set rules about who can prescribe TPOXX and how it can be used. Multiple state and territorial health departments requested TPOXX supplies; thus, clinicians wishing to use TPOXX should contact their local health department to learn whether supply is available and how to obtain it. This is different from physicians contacting product manufacturers to request access to a product, which is normally the case with expanded access.
Also different is the fact that the CDC decided to take upon itself the requirement, often left to individual physicians, to obtain IRB review and approval of expanded access. This means that instead of numerous IRBs across the country all reviewing requests to use TPOXX via expanded access in individual patients, a central IRB run by the CDC is handling this.
The CDC is also providing informed-consent documents (including in non-English languages and in a short form), something that normally would be left to the individual physician to develop with the help of the sponsor.
Furthermore, rather than each individual physician having to complete the required expanded access paperwork, CDC is allowing there to be only one submission from each institution where TPOXX is being used. These are laudable examples of CDC trying to streamline access to TPOXX.
There is one other unusual aspect of the TPOXX expanded access Program that raises a set of thorny issues concerning how expanded access should be handled and what its role should be. Though the CDC is requiring only a baseline intake form and a report of any serious adverse events that happen after use of TPOXX, it is asking for, on a voluntary basis, a patient diary, a clinical outcome form, photos of lesions, lesion samples, and pharmacokinetic samples for testing.
With this, this endeavor suddenly appears to be something more than clinical care of patients. Determining whether something is research or treatment is not always easy nor is there necessarily a single entity empowered to decide what activities fall into which category. In this case, the TPOXX program was likely deemed expanded access, not research, because the primary aim was to treat patients and the data collection component (other than reports of serious adverse events, which are required in expanded access) is voluntary.
However, colleagues and I have proposed that when data collection entails activities beyond those which would otherwise occur during the clinical care of the patient and/or the collection or sharing of patient data above and beyond that for public health or quality-control purposes, that the line has been crossed from patient treatment with some data collection to research and thus that such activities should be conducted as regulated clinical studies, not expanded access.
It is important to remember that clinical research is the most efficient way to answer questions of a product's safety and efficacy, and that the sooner such questions are answered, the sooner we can offer patients evidence-based medical care instead of our best guess. There is an ethical imperative to prioritize robust evidence-generating endeavors, like high-quality clinical trials, and this justifies limiting the size and scope of expanded access Programs to only those patients who are unable to participate in clinical trials of the investigational product. This is all the more urgent in the case of using TPOXX because the FDA approved this product under its animal rule. This means that a product's safety must be proven in humans but its efficacy is proven in animal models because it would be unethical or infeasible to conduct human efficacy studies. But owing to the monkeypox outbreak in the United States, it is now both feasible and ethical to study TPOXX's efficacy in humans.
According to ClincialTrials.gov, there is one actively recruiting, multisite TPOXX efficacy trial in the United States, STOMP. In my opinion, patients who have the ability to participate in this trial should be funneled to it and should be unable to receive the product via expanded access. This would be true for all situations in which there are coexisting clinical trials and Expanded Access Programs, but it is even more important in the situation of an epidemic, given past experiences with COVID-19 and Ebola virus disease, in which falling case counts over time imperiled the successful completion of trials and thus the generation of evidence concerning efficacy and safety.
At the same time, if necessary to enroll the number of participants needed to quickly obtain an understanding of TPOXX's safety and efficacy for monkeypox, the STOMP trial should broaden its number and variety of trial sites in order to make the opportunity to participate available to a larger number of individuals. According to ClinicalTrials.org, there will be 64 locations, spanning Alabama, California, Colorado, Connecticut, Florida, Georgia, Illinois, Maryland, Massachusetts, Michigan, Mississippi, Missouri, Nebraska, New Jersey, New York, North Carolina, Ohio, Pennsylvania, Tennessee, Texas, Washington State, and Puerto Rico. This is impressive, but it still leaves certain areas of the United States underserved. One possibility under discussion that would go a long way toward both promoting equity of access to the trial and, possibly, hasten trial enrollment and completion, is to roll out a remote option wherein the participants do not have to visit a clinical trial site.
STOMP is inclusive in regard to who may participate, permitting those younger than 18 years and those who are pregnant or breastfeeding. These are the sort of patient populations who are all too frequently excluded from clinical trials and in need of expanded access as an option; however, because they, too, deserve evidence-based medicine, it is preferable to include these types of patients in clinical trials to learn about TPOXX's effect on them. If other trials concerning TPOXX for monkeypox are established, they will hopefully share the STOMP trial's concern for enrolling diverse populations.
Expanded access can be confusing in that it is intended to provide medical treatment, but at the same time, it has some of the oversight that characterizes medical research. The divide between treatment and research is even more complicated when activities beyond those necessitated to treat a patient occur for the purposes of data generation, collection, and/or sharing.
Yet, a public health emergency, such as that posed by the monkeypox epidemic in the United States, is not an ideal time for making fine distinctions between various types of access to investigational medical products; the focus often is simply on trying to distribute as much of the product as possible.
In summary, it is important for us to remember that there is good reason to prioritize clinical research over nontrial access to unproven medical products, and that it is not only ethical but also appropriate to limit expanded access to TPOXX so as to increase enrollment in the trial, which will allow us to evaluate the utility of this product in an indication that has not been approved by the FDA.
Images: NYU Grossman School of Medicine
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Cite this: Expanded Access for TPOXX (Tecovirimat) for Treatment of Monkeypox: An Explainer - Medscape - Oct 10, 2022.