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Oct2022

Expanded Access for Tecovirimat (TPOXX): An Explainer for IRB and other regulatory professionals
IRB and other research regulatory professionals in the United States may not be familiar with Tecovirimat (TPOXX). This explainer is intended to acquaint them with basic facts about TPOXX and the efforts currently underway to 1) use it to treat patients with monkeypox and 2) collect efficacy and safety information concerning such use. This explainer deals with both the US Centers for Disease Control and Prevention (CDC)-run Expanded Access program for TPOXX and the only trial of Tecovirimat as a treatment for monkeypox currently underway in the United States, the Study of Tecovirimat for Human Monkeypox Virus  (STOMP). This explainer is up-to-date as of October 25, 2022.

What is TPOXX?
Tecovirimat (TPOXX) is an antiviral approved by the FDA for the treatment of smallpox. Notably, it was approved under the animal rule, in which FDA approval is granted based on safety data derived from human subjects but efficacy data from animal studies. The animal rule is utilized when human efficacy studies are deemed unethical or infeasible, as would be the case for testing a treatment for smallpox, an eradicated disease.

Is TPOXX FDA-approved to treat monkeypox?
No, TPOXX’s FDA-approved indication is only for the treatment of smallpox. Normally, physicians are able to prescribe FDA-approved medical products “off-label” for other uses. This is not possible for monkeypox, as will be explained below.

Why is TPOXX handedly differently from other FDA-approved drugs?
When TPOXX was originally approved by the FDA for the treatment of smallpox, a key stipulation was that it could only be sold to the U.S.’s Strategic National Stockpile, maintained by the Department of Health and Human Services (HHS), for use in public health emergencies. HHS tasked the CDC with setting rules about how TPOXX is used and who can use it. The CDC has decided that, because the FDA approval of TPOXX pertains only to smallpox, the drug will only be available through specific FDA-regulated pathways, as will be explained below. Thus, physicians cannot individually prescribe or use TPOXX without involving CDC or the health departments that CDC is using to distribute TPOXX.

If TPOXX isn’t approved for monkeypox, why is it being used?
On August 4, 2022, HHS Secretary Xavier Becerra declared monkeypox a national public health emergency, following the lead of the  World Health Organization and several U.S. states and major cities. As of October 24, 2022, there have been 28,004 cases and 6 deaths from monkeypox reported in the US.

Although there is no FDA-approved treatment for monkeypox, TPOXX’s approval for smallpox was based on drug tests on animals infected with monkeypox and rabbitpox. This research led the European Medicines Agency (EMA) to approve TPOXX for not just the treatment of smallpox but also monkeypox and cowpox. In contrast, the FDA did not expand its approval beyond the manufacturer’s requested indication of just smallpox. Neither the FDA nor EMA approvals had access to human efficacy data for TPOXX, only efficacy data in animals.

What are the specific FDA-regulated pathways that enable patient access to TPOXX?
There are two pathways available: clinical trials and expanded access.

What clinical trials of TPOXX for monkeypox are available?
There is currently one active trial of TPOXX for monkeypox in the United States. The Study of Tecovirimat for Human Monkeypox Virus (STOMP) is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), and will have 64 study locations enrolling 530 participants; however, a majority of trial sites are not yet recruiting. According to STOMP’s entry on Clinicaltrials.gov, trial participants will be randomized 2:1 to receive either TPOXX or placebo. Once enrolled, study drug administration will be for 14 days. Participants will self-monitor skin and/or mucosal lesions daily through 29 days or resolution (whichever comes first), complete a daily diary of symptoms, and complete a daily numerical rating scale for pain assessment. Participants will be seen weekly through day 29 for assessment of monkeypox disease, safety assessments, sample collecting, and swabbing of new lesions. Participants will be seen at day 57 to assess for any new lesions occurring after initial resolution of disease.

STOMP also has an open-label arm, intended for participants with severe disease, significant skin conditions, severe immune suppression, or who are pregnant or breastfeeding, less than 18 years of age, or receiving a potent inducing concomitant medication.

Participants in the active trial arms who progress to severe monkeypox disease will be seen in person for a confirmation of progression. If severe disease is confirmed, participants will stop blinded study treatment and start a 14-day course of open-label tecovirimat. Participants reporting severe pain 5 days after randomization will likewise stop blinded study treatment and start a 14-day course of open-label TPOXX.

What is expanded access and how does it work?
Expanded access is an FDA-regulated pathway that permits the use of unapproved medical products to treat patients with a serious or immediately life-threatening disease or condition who have no alternative options, including no options to participate in clinical trials. (Lack of desire to participate in a clinical trial is not sufficient; expanded access is only for patients who cannot participate.) In contrast to clinical trials, which are intended to produce generalizable knowledge about a particular intervention, expanded access intends to treat individual patients. This distinction is important, as the conflation of these two aims in practice can hinder the conduct of research and the ultimate goal of establishing safety and efficacy of a particular unproven intervention.

In order for a patient to qualify to receive an intervention through expanded access, certain eligibility criteria must be satisfied, as mandated by U.S. federal regulations. The patient must be suffering from a disease or condition for which there are no FDA-approved treatments (or approved treatments have already been tried) and must be ineligible for ongoing clinical trials. These requirements are in place to ensure that clinical trials and the generation of robust evidence about a particular unproven intervention are prioritized over its use as (an unproven) treatment through expanded access. Once a treating physician has determined that their patient satisfies these criteria and could benefit from a particular unproven intervention, they may ask the manufacturer (often a pharmaceutical company) to provide their product through expanded access. Manufacturers, as the ultimate gatekeepers to their products, are not obligated to satisfy expanded access requests and may either decide on a case-by-case basis or open an Expanded Access Program (EAP) to facilitate access for a cohort of patients. If an expanded access request is granted, federal regulations also require the involvement of an IRB, to ensure proper patient protection measures are taken, and the FDA, to review the case and ensure that use of the unproven intervention is reasonably safe.

If TPOXX is already FDA-approved for smallpox, why can’t it be prescribed for monkeypox off-label?
While FDA-approved as a treatment for smallpox, TPOXX is not available except as permitted by CDC. The CDC is thus playing a similar role to that of the product manufacturer in more typical expanded access cases—e.g., deciding whether or not to grant requests for a product’s use. However, unlike typical expanded access cases, the CDC is pre-positioning supplies of TPOXX within state and regional health departments that are then able to allocate the supply to clinicians and care facility pharmacists.

Is IRB approval required to permit participation in the TPOXX expanded access program?
IRB review and approval is required for use of the expanded access pathway. A central IRB, run by the CDC, is reviewing all expanded access requests for TPOXX, in lieu of individual IRBs at each of the institutions where TPOXX use is requested. In addition to reducing burden on institutions, this enables clinicians unaffiliated with an IRB to treat patients via the expanded access program. The CDC is also providing informed consent documents (in multiple languages and in both traditional and short form versions) and has streamlined expanded access paperwork requirements such that each institution using TPOXX for its patients need only submit once on behalf of all uses, instead of per each use. These measures have facilitated fairly easy access to TPOXX for patients in need.

Since there is a central IRB, does my institution’s IRB need to do anything?
This will depend on your institution’s policies. For example, some institutions require that all research and expanded access uses be submitted to the IRB for administrative tracking purposes, even if an external IRB is responsible for the review.

What should a clinician without research/expanded access experience know about participating in the TPOXX Expanded Access Program?
As noted earlier, the CDC has streamlined the expanded access paperwork, but some is still required. For each facility where TPOXX will be used, one signed FDA Form 1572 (in which the treating physician commits to complying with FDA requirements) and the treating physician’s CV are required to be submitted to the CDC. As the CDC is only requiring one form/CV per facility, other physicians at that facility will not have to submit this paperwork.

For each participant, the patient (or their parent/guardian or legally authorized representative) is required to sign a consent form, and the treating physician or designee should complete the Patient Intake Form prior to TPOXX initiation. In the event of a life-threatening or serious adverse event associated with TPOXX, a MedWatch Form needs to be completed and returned to the CDC within 72 hours. There are additional optional materials that participants will be asked to provide. For more information, visit the CDC’s Information for Healthcare Providers on Obtaining and Using TPOXX (Tecovirimat) for Treatment of Monkeypox page.

Is there anything else unusual about the TPOXX Expanded Access Program?
The CDC is asking patients treated with TPOXX to submit information beyond the serious adverse event reporting required for all expanded access cases. Although these are optional, the CDC asks for a patient diary detailing each of the 14 days TPOXX is taken, a clinical outcome form, as well as blood and lesion sampling during and after use of TPOXX. This data collection goes beyond patient care and thus starts to resemble a clinical trial; however, the goal of expanded access is treatment, not the generation or collection of generalizable data. This data collection effort puts the TPOXX expanded access program in a gray area between research and treatment. While some potentially interesting data is being collected, this uncontrolled data is subject to bias and is not as robust as the data collected from a randomized controlled trial.

How should clinicians decide whether to enroll new patients in the STOMP trial or the TPOXX expanded access program?
Expanded access is limited to patients who have no other options, including that of participating in a clinical trial. The STOMP trial has numerous trial sites and lenient eligibility criteria; nevertheless, several of its trial sites are not yet recruiting. Even where trial sites are actively recruiting, it is quite possible that some patients would be ineligible to participate for practical reasons (e.g., they live too far away, lack financial or logistical ability to make required trial visits, etc.) or because they do not fit the trial’s criteria. As they are ineligible for the STOMP trial, these patients are likely eligible for, and should be channeled to, the expanded access program, as these are the very patients for whom it was created.

Since the expanded access program opened before the STOMP trial, it is highly likely that there are patients who meet STOMP trial eligibility criteria in the expanded access program. When the STOMP trial was not yet open, treating those patients through the expanded access program would have been appropriate, as there was no research option. Now that there is a research option, it is not appropriate for new trial-eligible patients to be enrolled in the expanded access program. If participation is feasible geographically and logistically, trial-eligible patients should be referred to the STOMP trial or other trials, if any such open.

There have been anecdotal reports of institutions declining to participate in the STOMP trial because they believe it is unethical to enroll patients in a placebo-controlled trial when there is a product available for use. However, as described before, TPOXX is not FDA-approved for monkeypox, and its approval as an antiviral is based on animal efficacy data. As such, learning about its efficacy in humans with monkeypox is still an ethically and scientifically valid area of inquiry. There is no ethical obligation to treat patients with an intervention that has not been proven safe and effective for their condition. On the other hand, there is an ethical obligation to prioritize the rapid collection of robust safety and efficacy data, both in order to evaluate the worth of the unproven intervention and to practice evidence-based medicine. The STOMP trial also incorporates a rescue plan, described above, for trial participants who suffer disease progression or severe pain after trial day 5.

Why should patients be channeled to trials if TPOXX is available through the expanded access program?
Going back to the required criteria for expanded access, patients eligible for enrollment in the STOMP trial (and other studies of TPOXX efficacy, if they open) and who have the practical ability to participate should be referred to trials, not the expanded access program. It is not always easy to prioritize clinical trial enrollment when disease is spreading quickly and treatment is needed. From the patient perspective, a potentially helpful treatment now could be seen as preferable to a proven intervention at some point in the future. Still, it is vital that clinical research be prioritized in these situations, so as to identify an effective and safe intervention as quickly as possible. When it comes to TPOXX, the FDA has not approved it as a treatment for monkeypox; the collection of sufficiently robust data supporting this use could lead to a label expansion, facilitating its use in future monkeypox outbreaks.

Conclusion
In Ebola, COVID-19, and now monkeypox, we have seen that declining case counts hinder the enrollment and completion of the clinical trials needed to vet unproven interventions. In such public health emergencies, we see non-trial access to unproven interventions as an additional threat to clinical research. As such, public health officials, medical directors, clinicians, IRBs, and research regulators need to ensure both the prioritization of research on the efficacy of TPOXX for monkeypox and that patients who are eligible for such research are referred accordingly, rather than permitted into the expanded access program intended for those for whom research is not a viable possibility.

As mentioned, the TPOXX expanded access program has several research-esque aspects, including specimen sampling and outcome reporting. However, the data collected from expanded access programs will be of inferior quality to data collected in well-conducted clinical trials; as such, there is a social need to channel eligible patients into trials rather than the expanded access program, which should be reserved for those individuals who are unable to participate in clinical research.

The STOMP trial (and any future trials for TPOXX) should incorporate ways to make it easier for patients to participate remotely. This will help ensure the prioritization of the trials that will generate high-quality efficacy data to enable assessment of the value of TPOXX for the treatment of monkeypox. From an ethical standpoint, allowing remote trial participation will promote equity of access; furthermore, this would permit the trial to enroll more quickly and achieve a determination of efficacy faster, which will, in turn, expedite the development of evidence-based practice for treating patients.


Authors:
John Massarelli, BA
Program Coordinator
Division of Medical Ethics
Department of Population Health
NYU Grossman School of Medicine

David Wallach, MPH, CIP
Director, Regulatory Affairs & Business Operations
NYU Grossman School of Medicine

Alison Bateman-House, PhD, MPH, MA
Assistant Professor
Division of Medical Ethics
Department of Population Health
NYU Grossman School of Medicine

Acknowledgement statement:
The authors would like to thank Dr. Melissa Epstein, PhD, MBE, CIP and Kevin Nellis, MS for their contributions to this work.

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