The guidance, intended to support companies racing to develop treatments for the novel coronavirus, outlines best practices for designing clinical trials that the FDA will consider sufficient to support approval. However, the guidance also notes several areas in which the agency is not yet providing recommendations, indicating that changes are yet to come.
By Laura DiAngelo, MPH
Executive IQ Brief
- How Things Work Now: In general, clinical trials are tightly controlled, with research teams required to adhere to FDA-reviewed and IRB-approved Clinical Protocols operating under an approved investigational new drug (IND) application. Study designs and protocols dictate how the trial will be run and operated and must be appropriately designed to ensure that the agency accepts data generated as “substantial evidence” to support approval. However, with increased uncertainty during the COVID-19 pandemic, the FDA has recently issued policies outlining specific considerations for operating a trial during the outbreak.
- What’s New: With the increased need for research and treatments to respond to COVID-19, on May 11 the FDA issued new guidance providing general recommendations for sponsors developing treatments or preventive measures for the novel coronavirus. Although the recommendations in the guidance are most applicable to drugs with an antiviral or immunomodulatory mechanism of action—that is, they attack the virus itself or modify the function of the immune system—the agency maintained that the recommendations could be broadly applicable for other mechanisms of action as well. The guidance provides recommendations on population selection, trial design and statistical considerations and efficacy endpoints.
- Impact: With a significant number of clinical trials for COVID-19 already underway, the guidance isn’t likely to change anything significant for sponsors in its first iteration. However, as industry has seen with the FDA’s guidance on operating trials during the pandemic, the guidance is likely to be updated iteratively.
Companies are required to demonstrate that their product is safety for use and effective when used as intended. This demonstration is done through the submission of “substantial evidence,” defined under the Federal Food, Drug, and Cosmetics (FD&C) Act as:
“Evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.”
Traditionally, the FDA has interpreted the need for “well-controlled investigations” to mean at least two clinical trials for new drugs, or applications for supplemental indications.
In general, clinical trials are tightly controlled, with research teams required to adhere to FDA-reviewed and IRB-approved Clinical Protocols operating under an approved investigational new drug (IND) application. Protocols define how the trial is to be run and operated, including how the researchers intend to interact with participants, how measurements will be taken, and the tools that will be used. The protocol is intended to ensure that the variable being researched—the drug or therapy—is the one causing a potential effect, rather than external factors such as methodology changes. Statistical validity is near paramount to the FDA when considering evidence for approval but remains second to participant safety.
There are currently no FDA-approved drugs to treat COVID-19, and the standard-of-care for treatment relies on clinical management of symptoms and supportive care (e.g., supplemental oxygen, mechanical ventilation).
The FDA has released guidance outlining how sponsors with ongoing trials—or those who are considering ramping up trials—should consider the design and operation of studies as they face unprecedented disruptions. Additionally, the agency opened up a new COVID-19-specific pathway for reviewing possible therapies, the Coronavirus Treatment Acceleration Program.
There are more than 130 clinical trials already underway for products intended to treat COVID-19, according to the CTAP webpage, and more than 400 currently in the planning stage. However, clinical research on COVID-19 has been limited to date. There are still several unknowns about the natural history of the disease, leading to questions from researchers and providers about how to best to focus their response efforts. For example, a new article in the Journal of the American Medical Association (JAMA) on May 11 highlights the lack of clinical research in the durability of any recovery, as well as if an individual would potentially be susceptible to reinfection.
With the increased need for research and treatments to respond to COVID-19, on May 11 the FDA issued new guidance providing general recommendations for sponsors developing treatments or preventive measures for the novel coronavirus.
The guidance does not apply to convalescent plasma or vaccines, which are regulated as biologics under the PHS Act. Although the recommendations in the guidance are most applicable to drugs with an antiviral or immunomodulatory mechanism of action—that is, they attack the virus itself or modify the function of the immune system—the agency maintained that the recommendations could be broadly applicable for other mechanisms of action as well.
The guidance provides recommendations on population selection, trial design and statistical considerations and efficacy endpoints.
As in the agency’s standing guidance on conducting non-COVID-specific trials during the pandemic, safety of participants and staff is highlighted as a significant priority for developers.
In its guidance, the FDA outlines specific recommendations for drug development programs for preventive measures and for treatment measures. For sponsors developing treatments, the FDA recommends that sponsors document the participant’s diagnosis using a laboratory diagnostic. Additionally, sponsors would need to categorize the baseline severity of participants, with the agency providing a series of four severity levels (asymptomatic, mild, moderate, severe, and critical) and associated biomeasures and definitions for each level as an example. If the trial enrolls patients with different severity levels, sponsors should conduct interaction analyses by baseline severity to identify the impact on each subgroup.
In prevention trials, sponsors are urged to conduct trials in places where participants are more likely to be exposed to COVID-19, either geographically or in populations like first responders or health care workers. If the sponsor chooses to run trials in geographic hot-spots, they should be prepared to open new sites and close others as the incidence waxes and wanes.
Diversity remains a key issue for the FDA in designing trials, especially for COVID-19 which has been demonstrated to have more seriously impact geriatric populations and black/indigenous people of color (BIPOC). The agency urges sponsors to include older adults, racial and ethnic minority persons, and those with co-morbidities such as renal or hepatic impairment should be prioritized in trial enrollment, given the widespread prevalence and increased risk of adverse events from COVID-19 in those populations.
The agency also notes that there is a need for data on COVID-19 prevention and treatment data on children, pregnant and lactating individuals and outlines some considerations, although not direct recommendations, on their trial enrollment. The agency encourages that sponsors include pregnant and lactating individuals in phase 3 trials “if appropriate,” and states that “children should not be categorically excluded.” For pediatric study plans (required under the Pediatric Research Equity Act (PREA) for all new drugs, dosing regimens, or indications), the agency indicates that it will express flexibility, stating that it “intends to work with sponsors to reach an agreement on the initial pediatric study plan” as quickly as possible to support development.
The need for safety and efficacy data in diverse, broad populations is increasingly a focus of the agency, but is likely to be exacerbated by the novel coronavirus. If the pivotal trial is small, with limited representation in the population, the agency could have trouble ensuring that the product is appropriate for use across a wide population. Any treatment for COVID is likely to be subject to massive need and demand by those affected by the virus. Limited data could limit the safe and effective use of the medicine, such as those in vulnerable populations.
The agency does not recommend a specific trial size but notes that “to the extent possible,” sponsors should justify their sample size as part of their statistical considerations. It should be large enough to demonstrate safety and efficacy, but still allow for strong controls. The duration will need to rely on the types of patients included—for example, while sponsors could consider a four-week duration “sufficient” for outcomes in a ventilator-dependent population, longer durations would need to be considered for treatments for less-seriously-ill patients.
As in typical drug development, the FDA “strongly recommends” trials be designed as randomized, placebo-controlled, double-blind trials using a superiority design. Although patients with COVID-19 should be maintained on standard of care (including any anticipated use of other drugs, off-label use, or interventions), the FDA acknowledges that the standard of care is likely to change as more is known about the virus and best practices in treating it. If the investigational product is intended to be used in a certain population—such as hospitalized patients—then the trial should be designed with the investigational agent or the placebo control added to the standard of care in a superiority study with an add-on design. If the investigational treatment works in a similar way to the standard of care, sponsors should consider an active-comparator controlled study design.
For COVID-19 trial designs, the FDA noted that it would consider decentralized and/or platform trials appropriate “under certain circumstances,” but outlines its own limitations. Without more experience regarding these trial-types in the context of COVID, the agency states that it “may provide additional recommendations” in future iterations of the guidance.
If preclinical or preliminary evidence demonstrates a compelling case for the intervention’s safety and efficacy, sponsors should move directly into larger, appropriately designed trials. However, if that evidence is limited, sponsors can consider conducting a proof-of-concept trial or designing a trial with a prospectively planned futility stop criteria. Under this trial design, the proof-of-concept trial would expand into a larger, confirmatory trial if compelling evidence is generated.
In general, the FDA encourages sponsors to incorporate stop criteria into any trial design prospectively, in order to ensure that a trial is pulled, and participant safety is maintained in a quick and efficient manner.
To ensure statistical validity, while the trial “should aim to minimize missing data,” the FDA has maintained that it will be “flexible, where appropriate” in previous guidance. To mitigate the effects of, or potential for, missing data, the FDA encourages sponsors to use an independent data monitoring committee (DMC) to oversee trial integrity.
Aligning with general best practices, safety considerations should be incorporated into all trial designs. However, COVID-19 represents unique safety concerns. While the natural history of COVID-19 is still not well understood, the disease caused by the virus is associated with multi-system organ failure, with an estimated 5-15% of hospitalized COVID patients developing acute kidney injury according to some Chinese researchers (although additional studies are still needed). When designing trials for treatments, sponsors should incorporate significant safety considerations, including a standardized toxicity grading scale for those with severe COVID-19 or those with serious comorbidities and the potential for drug-drug interactions that increase toxicity risk.
Safety assessments should be performed regularly, although the cadence should be informed by the severity of the illness. Safety reporting for clinical trials that is otherwise required will still remain in effect. Additionally, sponsors are encouraged to limit in-person data collection, allowing for expanded use of remote patient monitoring. Best practices for these monitoring systems are outlined in the FDA’s risk-based monitoring approach, originally issued in 2013.
Although the relevance and appropriateness of the outcomes measures used in each trial will depend on the population studied and baseline severity, the FDA includes a list of important measures for both treatment and prevention trials.
For treatments, all-cause mortality, not developing respiratory failure, hospitalization, or time to sustained recovery could be appropriate. For prevention, the primary endpoint should be the incidence of infection over time or through a prespecified point.
However, a lack of understanding of the novel coronavirus has implications for endpoint selection as well. For example, virologic measures would be considered an acceptable endpoint in phase 2 trials but not as primary endpoints in phase 3, as the predictive relationship and best clinical practices for identifying clinically relevant virologic measurements have not yet been established.
To help ensure statistical validity, even if all-cause mortality is not selected as the primary endpoint, the agency maintains that analyses on this endpoint will be needed as all other endpoints could interfered with by the treatment effect.
For the primary efficacy analysis, the agency will accept statistical approaches including binary outcome analysis (yes or no), ordinal outcome analysis (rank-based approaches or proportional odds), or time-to-event analysis (hazard models).
Even if all-cause mortality is not the selected primary endpoint, the agency states that death should be incorporated into the endpoint as a highly unfavorable possible outcome–given that treatment for all other endpoints other than all-cause could be driven by non-mortality components rather than the effect of the drug.
With a significant number of COVID-related trials underway, much of the information in the guidance is unlikely to be a surprise to industry. However, the guidance does represent an opportunity for the agency to provide best-practice communications going forward.
The guidance is presented as a “discussion,” rather than concrete policies, and is likely to be updated regularly as new data and evidence becomes available about the virus and its impact. For example, data emerging from New York indicates that pediatric populations can face unique adverse events from a multi-system inflammatory syndrome that is considered linked to COVID, raising the need for more clarity on pediatric population studies. Additionally, as the virus’s natural history becomes better understood new endpoints could be introduced, including validation of virologic endpoints for phase 3 studies. Additional information about the impacts of COVID-19 on the body, such as on the lungs and kidneys, may also result in required monitoring in specific trials.
In addition, while the guidance represents the FDA’s ideal recommendations, the agency may also feel pressure to accept a wider range of less-than-ideal study designs and results. Political pressure, in particular, may prevent the agency from rejecting applications or calling for additional study in the same way that it ordinarily would for sub-par data.
The guidance is immediately in effect and will expire when the emergency is terminated, but the FDA will issue new guidance updating clinical trial operation more generally after its conclusion. Manufacturers can expect to see new guidance from the agency incorporating some of the policies within two months of the emergency lapsing. The agency has already taken steps in support of decentralized or platform trials and remote monitoring, which could be the types of policies that remain in effect after the public health emergency. However, as both the FDA—and AgencyIQ—have found, operational challenges still represent a significant issue for novel trial designs.